Fatty Acid Conjugates of Quetiapine, Process for Making and Using the Same

ABSTRACT

The presently described technology provides a novel class of prodrugs of quetiapine that can be synthesized by chemically conjugating fatty acids to quetiapine. Pharmaceutical compositions and methods of synthesizing conjugates of the present technology are also provided. Methods of treating patients with the compositions of the present technology are also provided.

RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S.application Ser. No. 13/043,764, filed on Mar. 9, 2011 which claimspriority to and benefit from U.S. Provisional Application Ser. No.61/312,977, filed on Mar. 11, 2010, the contents of both of which areincorporated herein by their references in their entireties.

BACKGROUND OF THE INVENTION

Quetiapine has been used in the treatment of severe mental illness inapproximately 70 countries including the US, Canada, most WesternEuropean countries, and Japan. Quetiapine is a dibenzothiazepinederivative with a relatively broad receptor binding profile. It hasmajor affinity to cerebral serotonergic (5-HT_(2A)), histaminergic (H1),and dopaminergic D₁ and D₂ receptors, moderate affinity to a₁- andα₂-adrenergic receptors, and minor affinity to muscarinergic M1receptors; it demonstrates a substantial selectivity for the limbicsystem. This receptor avidity profile with relatively higher affinityfor the 5-HT_(2A) receptor compared to the D₂ receptor is considered tobe, at least in part, responsible for the antipsychotic characteristicsand low incidence of extrapyramidal side-effects of quetiapine.

The efficacy of quetiapine in reducing positive and negative symptoms ofschizophrenia has been proven in several clinical trials withplacebo-controlled comparators. Quetiapine has also demonstrated robustefficacy for treatment of cognitive, anxious-depressive, and aggressivesymptoms in schizophrenia. Quetiapine also has proven efficacy andtolerability in the treatment of moderate to severe manic episodes, andin the treatment of juveniles with oppositional-defiant or conductdisorders, and in the geriatric population with dementia. Data indicatethat quetiapine is also effective in the treatment of bipolar depressivesymptoms without increasing the risk of triggering manic episodes, andin borderline personality disorder. In comparison with otherantipsychotics, quetiapine has a favorable side-effect profile.

In clinical trials, only small insignificant prolongations of the QTinterval were observed. Weight-gain liabilities and new-onset metabolicside-effects occupy a middle-ground among newer antipsychotics. As aresult of its efficacy and tolerability profile, quetiapine has becomewell established in the treatment of schizophrenia and other psychiatricdisorders.

Recently though, in addition to large interindividual variability andweight gain, reports surfaced on treatment emergent diabetes (TED),associated with chronic administration of quetiapine. Additionally, thetherapeutical dose of quetiapine is relatively high, leading to the needof making pharmaceutical compositions with relatively highconcentrations of the active ingredient (up to 60%). Making tablets ofsuch a high concentration of the active pharmaceutical ingredient (API)is difficult, particularly due to the bad tabletting properties of theAPI.

Therefore, an advantageous alternative would be a formulation thatallows for better bioavailability of the drug, and avoids the need forrepeated administration thereby helping in regimen adherence byotherwise reluctant psychiatric patients. The formulation wouldpreferably exhibit a desired release profile that can lower the totalnecessary therapeutical dose and/or reduce side-effects such as TEDand/or weight gain.

BRIEF SUMMARY OF THE INVENTION

The present technology is directed to a novel class of prodrugs ofquetiapine that can be synthesized by chemically conjugating fatty acidsto quetiapine. The chemical bond between these two moieties isestablished in one aspect, by reacting the primary hydroxylfunctionality of quetiapine or any one of its active metabolites ornon-binding electrons of its active metabolites with the carboxyl groupof the fatty acids, thereby creating an ester conjugate or tertiaryamide conjugate.

In one embodiment, the invention provides a composition for treating apsychiatric disorder such as schizophrenia, bipolar disorder,obsessive-compulsive disorder, post-traumatic stress disorder, restlesslegs syndrome, autism, alcoholism, depression, insomnia or Tourettesyndrome in a subject, comprising a conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine), an active metabolite or derivative thereof and at leastone fatty acid such as a saturated fatty acid in one aspect, or amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid or a combination thereof in otherdiscrete aspects, as well as a salt thereof, a derivative thereof, ortheir combination. In another embodiment, the composition is formulatedfor oral, sublingual, transdermal, intrathecal or suppositoryadministration wherein quetiapine or an active metabolite thereof suchas N-desalkyl-quetiapine (norquetiapine; nor QTP) and a fatty acid suchas valproate is present in the composition in an amount of from about 1to about 2000 mg/dose based on equimolar weight of unconjugatedquetiapine, or unconjugated active metabolite. Oral administration iscarried out in certain embodiments using a tablet, capsule, caplet,pill, powder, troche, lozenge, slurry, liquid solution, suspension,emulsion, elixir or oral thin film (OTF), each a discrete embodiment ofthe form of oral administration.

In another embodiment, the invention provides quetiapine or any one ofits active metabolites or derivatives, conjugated to at least one fattyacid as represented by any one of the structures of general formulasI-IV:

a pharmaceutically acceptable salt thereof, a derivative thereof or acombination thereof, wherein “R” is a fatty acid side-chain selectedfrom the group consisting at least one of the fatty acids set forth inTables I-VII.

In another embodiment, the invention provides a method of conjugatingquetiapine or an active metabolite thereof such as 7-hydroxy-quetiapine(7-OH-QTP) and at least one fatty acid such as a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid such asdocosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid or a combination thereof, comprisingthe steps of: in the presence of a base such as 4-methylmorpholine (NMM)or 4-(dimethylamino)pyridine (DMAP), attaching a fatty acid wherein thefatty acid has an optionally protected functional moiety therein, toquetiapine or its active metabolite whereby the functionalized fattyacid is protected with tert-butyloxycarbonyl (Boc) in one embodiment;followed by deprotecting the functionalized moiety on the fatty acid,thereby conjugating quetiapine or an active metabolite thereof and atleast one fatty acid.

In one embodiment, the invention provides a method of increasing therelative bioavailability of quetiapine or an active metabolite thereofsuch as nor QTP or 7-OH-QTP, comprising the step of conjugatingquetiapine or its active metabolite to at least one fatty acid such as asaturated fatty acid such as valproic acid, a monounsaturated fatty acidsuch as palmitoleic acid, a polyunsaturated fatty acid such as DHA orEPA, or a combination thereof, thereby modulating the hydrophobicity,solubility, improving absorption, altering metabolic pathways or theircombination of the conjugated quetiapine or the active metabolitethereof, resulting in certain embodiments, in a higher maximum observedblood plasma concentration (C_(max)) and/or area under the curve (AUC)and/or longer or similar amount of time after administration at whichC_(max) occurs (T_(max)) values compared to those produced byunconjugated quetiapine when administered at equimolar doses. Increasedbioavailability may also result in: reduced interindividual variabilityin one embodiment; decreased number and/or amount of active, inactive,toxic or non-toxic metabolites; increased number and/or amount of activemetabolites produced by unconjugated quetiapine or its active metabolitein other discrete embodiments of the outcome of increasedbioavailability resulting from the conjugation of quetiapine or theactive metabolite and at least one fatty acid.

In another embodiment, the invention provides a method of treating apsychiatric disorder requiring the binding of dopamine receptor(s),serotonin receptor(s), or histamine receptor(s) or a combination orpermutation thereof in a subject such as human or mammal, comprising thestep of orally, intrathecally transdermally or rectally administering tothe subject a composition comprising a therapeutically effective amountof about 1-2000 mg/dose based on equimolar weight of unconjugated API ofquetiapine or an active metabolite thereof such as7-hydroxy-N-desalkyl-quetiapine, conjugated to at least one fatty acidsuch as a saturated fatty acid, a monounsaturated fatty acid, apolyunsaturated fatty acid, an acetylenic fatty acid, a substitutedfatty acid, a heteroatom containing fatty acid such as colneleic acid, aring containing fatty such as ladderane-butanoic acid or a combinationthereof, a pharmaceutically acceptable salt or derivative thereof,thereby binding a dopamine receptor, a serotonin receptor, histaminereceptor or any permutation combination thereof. In one embodiment, theinvention provides a method of treating schizophrenia or bipolardisorder in a subject in need thereof, comprising the step ofadministering to the subject a composition comprising a therapeuticallyeffective amount of quetiapine or an active metabolite thereof,conjugated to at least one fatty acid such as7-hydroxy-N-desalkyl-quetiapinyl-octanoate, or7-hydroxy-quetiapinyl-valproate, a pharmaceutically acceptable salt, orderivative thereof, thereby binding to a dopamine receptor, a serotoninreceptor, or both and treating schizophrenia or bipolar disorder.

In one embodiment, the invention provides a quetiapine conjugatetransdermal therapeutic system, comprising a quetiapine conjugatereservoir comprised essentially of a) a gelling agent that is selectedfrom the group consisting of carbomer, carboxyethylene, polyacrylicacid, cellulose derivatives, ethyl cellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, natural gums, arabic,xanthan, guar gums, alginates, polyvinylpyrrolidone derivatives,polyoxyethylene polyoxypropylene copolymers, chitosan, polyvinylalcohol, pectin, or veegum; and b) quetiapine, an active metabolite orderivative thereof and therapeutically acceptable salts thereof, andmixtures thereof; conjugated to at least one of a fatty acid describedherein that functions as permeation enhancer. In one embodiment, thefatty acid functioning as permeation enhancer is a short-chain fattyacid (SOFA) such as butyric acid, a medium-chain fatty acid (MCFA) suchas caprylic acid, a long-chain fatty acid (LCFA) such as oleic acid, ora combination thereof. In another embodiment, the fatty acid functioningas permeation enhancer is a saturated fatty acid, a monounsaturatedfatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, or a ringcontaining fatty acid, or a combination thereof. In another embodiment,the fatty acid functioning as permeation enhancer is a fatty acidfunctionalized to be cross-linked to at least one other functionalizedfatty acid which is optionally conjugated to quetiapine, an activemetabolite or derivative thereof, or their combination. In anotherembodiment, the cross-linked fatty acids, at least some of which areconjugated to quetiapine, an active metabolite or derivative thereof, ortheir combination, form a polymeric gel. In another aspect, thecross-linked fatty acid is a polyunsaturated fatty acid such asα-linolenic acid, a polyhydroxy fatty acid, and epoxy containing fattyacid or their combination. In one embodiment, the transdermal systemfurther comprises a non-permeable backing and a permeable membranelocated between the release matrix and a site of interest on the skin ofa subject in the form of a transdermal patch with an impermeable coverlayer and removable protection layer, wherein the conjugate ofquetiapine or an active metabolite and/or an active derivative thereofand at least one of a saturated fatty acid, a monounsaturated fattyacid, a polyunsaturated fatty acid, an acetylenic fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid, across-linked fatty acid, a salt thereof, a derivative thereof or theircombination is present in an amount that produces plasma concentrationsof quetiapine, its active metabolite and/or active derivative thereofbetween about 89% and about 115% of the plasma concentrations achievedafter oral administration of an amount of between about 1 mg and about3000 mg per unit dose.

In another embodiment, the invention provides for the use of atherapeutically effective amount of a conjugate of quetiapine, itsactive metabolite and/or active derivative and/or their combination; anda saturated fatty acid such as valproic acid, a monounsaturated fattyacid, a polyunsaturated fatty acid, an acetylenic fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid, across-linked fatty acid or a combination thereof; in a medicament forthe treatment of a disorder associated with serotonin, dopamine orhistamine dysfunction in a subject in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood from a reading of the followingdetailed description taken in conjunction with the figures and examplesin which like reference designators are used to designate like elementsor findings, and in which:

FIG. 1 shows an oral PK rat study comparing plasma concentrations ofquetiapine produced by unconjugated quetiapine and by the valeric acid(valerate-QTP) and caprylic acid (caprylate-QTP) conjugates;

FIG. 2 shows an oral PK rat study comparing plasma concentrations ofquetiapine produced by unconjugated quetiapine and by the caproic acidconjugate (caproate-QTP);

FIG. 3 shows oral PK rat study comparing plasma concentrations ofquetiapine produced by unconjugated quetiapine and by the capric acidconjugate (caprate-QTP);

FIG. 4 shows oral PK rat study comparing plasma concentrations ofquetiapine produced by unconjugated quetiapine and by the butyric acidconjugate (butyrate-QTP);

FIG. 5 shows a schematic of the process of synthesis of fattyacid-Quetiapine conjugate.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to quetiapine conjugatecompositions, their synthesis and use. In another embodiment, theinvention is directed to quetiapine conjugates with saturated,monounsaturated, polyunsaturated, acetylenic, substituted, heteroatomcontaining, ring containing fatty acids or their combination, theirsyntheses and use in therapeutic compositions for the treatment ofpsychiatric disorders.

Quetiapine:

is an atypical antipsychotic in the sub-class of multi-actingreceptor-targeted antipsychotics (MARTA). As such, it exhibitsantagonist activity at the dopamine D₂ and D₁ receptors, the serotonin5-HT₂ and 5-HT_(1A) receptors, the adrenergic α₁ and α₂ receptors andthe histamine H₁ receptor. While the modulation of the dopamine andserotonin receptors are thought to be responsible for the therapeuticactivity of quetiapine, the affinity of quetiapine to the histamine andadrenergic receptors may cause of some of its side-effects, particularlyits somnolent and hypotensive effects.

Quetiapine is currently approved for the following indications:

-   -   Acute and maintenance treatment of schizophrenia.    -   Acute depressive episodes associated with bipolar disorder.    -   Acute manic or mixed episodes associated with bipolar I disorder        as monotherapy and as an adjunct to lithium or divalproex        therapy.    -   Maintenance treatment of bipolar I disorder as adjunct therapy        to lithium or divalproex.

Quetiapine has also shown acceptable efficacy in some off-labelindications that include obsessive-compulsive disorder, post-traumaticstress disorder, restless legs syndrome, autism, alcoholism, depressionand Tourette syndrome. It has been used as sedative for patients withsleep or anxiety disorders.

In one embodiment, the compositions comprising the prodrugs providedherein may be administered for the treatment of schizophrenia or bipolardisorder or for any condition that may require the blocking of dopamineor serotonin receptors.

The term “prodrug”, as used herein, refers in one embodiment to ametabolic precursor of a compound of the conjugated quetiapine providedherein, which is pharmaceutically acceptable. A prodrug may be inactivewhen administered to a subject but is converted in vivo to an activecompound. In one embodiment, the term “active metabolite”, refers to ametabolic product of quetiapine that is pharmaceutically acceptable andeffective. In another embodiment, the term “active metabolite” refers toa metabolic product of quetiapine that is effective for ameliorating,treating or preventing schizophrenia, bipolar disorder,obsessive-compulsive disorder, post-traumatic stress disorder, restlesslegs syndrome, autism, alcoholism, depression, insomnia or Tourettesyndrome.

Prodrugs are often useful because, in some embodiments, they may beeasier to administer or process than the parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent isnot. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. An embodiment of a prodrug would be ashort-chain fatty acid, such as butyric acid bonded to a primaryhydroxyl group of quetiapine where the short chain fatty acid ismetabolized to reveal the active moiety. In certain embodiments, upon invivo administration, a prodrug is hydrolytically converted to thebiologically, pharmaceutically or therapeutically more active form ofthe compound. In certain embodiments, a prodrug is enzymaticallymetabolized by one or more steps or processes to the biologically,pharmaceutically or therapeutically active form of the compound. Toproduce a prodrug, a pharmaceutically active compound is modified suchthat the active compound will be regenerated upon in vivoadministration. The prodrug is designed to alter the metabolic stabilityor the transport characteristics of a drug in certain embodiments, tomask, ameliorate or reduce side-effects or toxicity, to improve theflavor of a drug or to alter other characteristics or properties of adrug.

In another embodiment, the term “active metabolite” refers to abiologically active derivative of a compound that is formed when thecompound is metabolized. The term “metabolized,” refers in oneembodiment to the sum of the processes (including, but not limited to,hydrolysis reactions and reactions catalyzed by enzymes, such as,oxidation reactions, de-esterification reactions and/or proteolysisreactions) by which a particular substance is changed by an organism.Thus, enzymes may produce specific structural alterations to a compound.In one embodiment, cytochrome P450 (CYP) catalyzes a variety ofoxidative and reductive reactions while some isoforms, such as CYP3A4are involved in de-esterification. Further information on metabolism maybe obtained from The Pharmacological Basis of Therapeutics, 9th Edition,McGraw-Hill (1996), incorporated herein by reference in its entirety.Metabolites of the compounds disclosed herein can be identified eitherby administration of compounds to a host under conditions allowing forthe determination of activity by the metabolite and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds. In some embodiments, acompound is metabolized to pharmacologically active metabolites.

In another embodiment, fatty acids conjugated to quetiapine create esterprodrugs that can release the active antipsychotic. The prodrugsprovided herein, alter the pharmacology, pharmacokinetics and/ormetabolism of quetiapine. As a result; by choosing suitable fatty acids,the bioavailability of quetiapine is increased. In one embodiment, theside-effect profile and inter-individual variability in plasmaconcentrations of the active are improved or reduced.

In one embodiment, provided herein is a novel class of prodrugs ofquetiapine, which is synthesized by chemically conjugating fatty acidsto quetiapine. The chemical bond between these two moieties isestablished by reacting the primary hydroxyl functionality of quetiapinewith the carboxyl group of the fatty acids, thereby creating an esterconjugate. In another embodiment, the fatty acids in the context ofprodrugs described herein are also referred to as “ligands” that areattached to the parent molecule (i.e., quetiapine).

In one embodiment, the conjugates of quetiapine, its active metaboliteand/or active derivative and/or their combination; and a saturated fattyacid such as valproic acid, a monounsaturated fatty acid, apolyunsaturated fatty acid, an acetylenic fatty acid, a heteroatomcontaining fatty acid, a ring containing fatty acid or a combinationthereof, creates a new class of drugs where both parent and ligand areactive pharmaceutical ingredients (API) and their conjugation creates asynergistic effect in their efficacy, reduced adverse side-effects andthe like.

Accordingly and in another embodiment, provided herein is a compositionfor treating a psychiatric disorder in a subject, comprising a conjugateof2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine), an active metabolite or derivative thereof and at leastone fatty acid, a salt thereof, a derivative thereof or a combinationthereof.

In one embodiment, the fatty acids used in conjunction with thecompositions, methods and systems described herein encompass fatty acidsof the broadest definition such as any that are natural and synthetic,short and long chain, saturated and unsaturated, straight chain andbranched, containing a ring or not, substituted and non-substitutedfatty acids. In another embodiment, the fatty acids of this inventionmay or may not include heteroatoms and keto groups.

Depending on the fatty acids conjugated to quetiapine, the prodrugformed can be either neutral, free acid, free base or pharmaceuticallyacceptable anionic or cationic salt forms or salt mixtures with anyratio between positive and negative components. These salt formsinclude, but are not limited to: acetate, L-aspartate, besylate,bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate,formate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate,D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate,gluceptate, D-glucuronate, hybenzate, isethionate, malonate,methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate,tosylate, thiocyanate, acefyllinate, aceturate, fattysalicylate,ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate,hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate,furate, fusidate, galactarate (mucate), galacturonate, gallate,gentisate, glutamate, glutarate, glycerophosphate, heptanoate(enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide,xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate,myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate,propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate,tannate, terephthalate, thiosalicylate, tribrophenate, valerate,valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate,esylate, glycolate, thiocyanate, and undecylenate.

In the compositions and methods described herein, the synthesizedprodrugs are designed to breakdown enzymatically, through hydrolysis orotherwise in vivo to quetiapine and the respective fatty acids or theirmetabolites. The fatty acids are preferably considered GenerallyRegarded As Safe (GRAS) or non-toxic at the released concentrations.

Without limiting the scope of this invention, examples of fatty acidsinclude common natural saturated fatty acids of the general formulaC_(n)H_(2n+1)COOH and a chain length of O₄ to C₃₀. In another embodimentfatty acids conjugated to quetiapine have short to medium chain lengthsof C₂ to O₈. Other embodiments include naturally occurring omega-3 andomega-6 unsaturated fatty acids.

Fatty Acids

Although this invention is not limited to naturally occurring fattyacids, in one embodiment, the term “fatty acids” refer to carboxylicacids that are related to or are found in their esterified form inplants and animals. While many naturally occurring fatty acids containan even number of carbons, the fatty acids described herein encompassany chain lengths with an odd or even number of carbons.

DEFINITIONS

is defined as a multi-set of residues whose members can be any of thesubstituents listed in the tables provided herein.

is a multiset, i.e., it can include multiple identical elements whichare in this case chemical substituents (e.g., two methyl groups).

The parameters m and m′ with m=|

| and m′=|

| are the cardinalities of the specific multisets and

and

thus describe the number of elements in

and

′.The parameters a, m, m′, n, n′, p, q, x, x′, y, y′ are integers.p describes the number of double bonds and q the number of triple bondsin a given carbon chain.

Classes of Fatty Acids

Straight/branched chain fatty acids:

C_(n)H_(2(n-p-2q)-m+1)

—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧1, 2(n−p−2q)+1≧m=|        |≧1

Carbon chain without substituent (

={H}):

C_(n)H_(2(n-p-2q)+1)—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧0

Saturated fatty acids:

C_(n)H_(2n+1)—CO₂H  General formula

-   -   n≧1

Monounsaturated fatty acids (cis or trans):

C_(n)H_(2n−1)+CO₂H  General formula

-   -   n≧2

Polyunsaturated fatty acids (any cis/trans):

C_(n)H_(2(n-p)+1)—CO₂H  General formula

-   -   n≧p+1, p≧2

Acetylenic fatty acids (any cis/trans):

C_(n)H_(2(n-p-2q)+1)—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧1

Carbon chain with substituent(s) (

≠{H}):

C_(n)H_(2(n-p-2q)-m+1)

—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧1, 2(n−p−2q)+1≧m=        ≧1

Alkyl group: alkylε

Hydroxyl group: OHε

Carboxyl group: CO₂Hε

Sulfate group: SO₄Hε

Methoxy group: OCH₃ε

Acetoxy group: OCOCH₃ε

Aldehyde group: CHOε

Halogens: any of F, Cl, Br, Iε

Nitro group: NO₂ε

Carbon chain with divinyl ether function:

H_(2(n-p-2q)-m+1)C_(n)—CH═CH—O—CH═CH—C_(n′)H_(2(n′-p′-2q′)-m′)

—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Carbon chain containing sulfur:

H_(2(n-p-2q)-m+1)C_(n)—S—C_(n′)H_(2(n′-p′-2q′)-m′)

—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Carbon chain with keto group:

H_(2(n-p-2q)-m+1)C_(n)—CO—C_(n′)H_(2(n′-p′-2q′)-m′)

—CO₂H  General formula

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Ring containing fatty acids:

Cyclopropane ring:

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Cyclopropene ring:

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Epoxy ring:

-   -   n≧2q+p+1, p≧0, q≧0, n′≧2q′+p′+1, p′≧0, q≧0, 2(n−p−2q)+1≧m=|        |≧1, 2(n′−p′−2q′)+1 m′=|        |≧1

Ladderanes:

-   -   n≧2q+p+1, p≧0, q≧1, 2(n−p−2q)+1≧m=|        |≧1; x, x′, y, y′=1 or 0

5- and 6-membered rings:

C_(n-a)X_(a)H_(2(n-z-p-2q)-m+1)

—CO₂H

-   -   a≧1, n≧a+2q+p+1, p≧0, q≧1, 2(n−a−p−2q)+1≧m=        ≧1

cyclopentyl/cyclopentenyl rings:

cyclohexyl/cyclohexenyl rings:

The broken line indicates the presence of a single or double bond.

Furan ring:

C_(n-a)X_(a)H_(2(n-a-p-2q)-m+1)

—CO₂ _(H)

-   -   a≧1, n≧a+2q+p+1, p≧0, q≧1, 2(n−a−p−2q)+1≧m=        ≧1

Examples of Fatty Acids

Without limiting the scope of this invention, provided herein areembodiments of fatty acids that can be attached to quetiapine via anester bond to form new prodrug entities.

In the following embodiments “shorthand designation” is an abbreviatedformula to describe the structure of fatty acids. The terminus of thisformula (after the “-”) indicates the number of carbons in then-carboxylic acid chain followed by the number of double bonds (in theformat c:d). Substituents on the core carbon chain are expressed by anumber and a letter code in ascending numerical order at the beginningof the formula. The number indicates the position of the substituent onthe n-carbon chain (numbering starts with the carboxyl group) and theletter code the type of substituent.

The definitions of the letter codes are: c=cis, t=trans, e=double bondwith undefined stereochemistry, y=triple bond, m=methyl, h=hydroxyl,dioic=dicarboxylic acid, Md=methylidene, a=alkyl, Sul=sulfate,OMe=methoxy, OAc=acetoxy, o=oxo, F=fluoro, Cl=chloro, Br=bromo,Nitro=nitro, k=keto; bridging atoms forming 3-membered rings within then-carbon chain are shown as: X-Yepoxy=oxygen bridging carbons atposition X and Y, X-YM=methylene bridging saturated carbons at positionX and Y (cyclopropyl), X-Ye=methylene bridging unsaturated carbons atposition X and Y (cyclopropenyl).

At the end of the formula (In parentheses) the position of the firstdouble bond is shown starting from the ω-carbon of the n-carboxylic acid(in the format n-d).

TABLE I Saturated fatty acids Systematic name Trivial name Formulamethanoic formic HCO₂H ethanoic acid acetic CH₃CO₂H propanoic acidpropionic CH₃CH₂CO₂H butanoic butyric CH₃(CH₂)₂CO₂H pentanoic valericCH₃(CH₂)₃CO₂H hexanoic caproic CH₃(CH₂)₄CO₂H heptanoic enanthicCH₃(CH₂)₅CO₂H octanoic caprylic CH₃(CH₂)₆CO₂H 2-propylpentanoic acidvalproic (CH₃((CH₂)₂))₂CHCO₂H nonanoic pelargonic CH₃(CH₂)₇CO₂H decanoiccapric CH₃(CH₂)₈CO₂H dodecanoic lauric CH₃(CH₂)₁₀CO₂H tetradecanoicmyristic CH₃(CH₂)₁₂CO₂H hexadecanoic palmitic CH₃(CH₂)₁₄CO₂Hheptadecanoic margaric (daturic) CH₃(CH₂)₁₅CO₂H octadecanoic stearicCH₃(CH₂)₁₆CO₂H eicosanoic arachidic CH₃(CH₂)₁₈CO₂H docosanoic behenicCH₃(CH₂)₂₀CO₂H tetracosanoic lignoceric CH₃(CH₂)₂₂CO₂H hexacosanoiccerotic CH₃(CH₂)₂₄CO₂H heptacosanoic carboceric CH₃(CH₂)₂₅CO₂Hoctacosanoic montanic CH₃(CH₂)₂₆CO₂H triacontanoic melissicCH₃(CH₂)₂₈CO₂H dotriacontanoic lacceroic CH₃(CH₂)₃₀CO₂H tritriacontanoicceromelissic (psyllic) CH₃(CH₂)₃₁CO₂H tetratriacontanoic geddicCH₃(CH₂)₃₂CO₂H pentatriacontanoic ceroplastic CH₃(CH₂)₃₃CO₂H

TABLE II Monounsaturated fatty acids Systematic Shorthand name Trivialname designation Formula  4-decenoic obtusilic  4c-10:1 (n-6)CH₃(CH₂)₄C═C(CH₂)₂CO₂H  9-decenoic caproleic  9c-10:1 (n-1)HC═CH(CH₂)₇CO₂H  5-lauroleic lauroleic  5c-12:1 (n-7)CH₃(CH₂)₅CH═CH(CH₂)₃CO₂H  4-dodecenoic linderic  4c-12:1 (n-8)CH₃(CH₂)₆CH═CH(CH₂)₂CO₂H  9-tetradecenoic myristoleic  9c-14:1 (n-5)CH₃(CH₂)₃CH═CH(CH₂)₇CO₂H  5-tetradecenoic physeteric  5c-14:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₃CO₂H  4-tetradecenoic tsuzuic  4c-14:1 (n-10)CH₃(CH₂)₈CH═CH(CH₂)₂CO₂H  9-hexadecenoic palmitoleic  9c-16:1 (n-7)CH₃(CH₂)₅CH═CH(CH₂)₇CO₂H  6-hexadecenoic sapienic  6c-16:1 (n-10)CH₃(CH₂)₈CH═CH(CH₂)₄CO₂H  6-octadecenoic petroselinic  6c-18:1 (n-12)CH₃(CH₂)₁₀CH═CH(CH₂)₄CO₂H  9-octadecenoic oleic  9c-18:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₇CO₂H  9-octadecenoic elaidic  9t-18:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₇CO₂H 11-octadecenoic vaccenic (asclepic) 11c-18:1(n-7) CH₃(CH₂)₅CH═CH(CH₂)₉CO₂H  9-eicosenoic gadoleic  9c-20:1 (n-11)CH₃(CH₂)₉CH═CH(CH₂)₇CO₂H 11-eicosenoic gondoic 11c-20:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₉CO₂H 11-docosenoic cetoleic 11c-22:1 (n-11)CH₃(CH₂)₉CH═CH(CH₂)₉CO₂H 13-docosenoic erucic 13c-22:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₁₁CO₂H 15-tetracosenoic nervonic 15c-24:1 (n-9)CH₃(CH₂)₇CH═CH(CH₂)₁₃CO₂H

TABLE III Polyunsaturated fatty acids: Systematic Name Trivial NameShorthand Designation Omega-3 Fatty Acids 7,10,13-hexadecatrienoic —7c10c13c-16:3 (n-3) octadecatrienoic α-linolenic (ALA) 9c12c15c-18:3(n-3) octadecatrienoic elaidolinolenic 9t12t15t-18:3 (n-3)octadecatetraenoic stearidonic (STD) 6c9c12c15c-18:4 (n-3)eicosatrienoic ETE 11c14c17c-20:3 (n-3) eicosatetraenoic ETA8c11c14c17c-20:4 (n-3) eicosapentaenoic timnodonic (EPA)5c8c11c14c17c-20:5 (n-3) docosapentaenoic clupanodonic (DPA)7c10c13c16c19c-22:5 (n-3) docosahexaenoic cervonic (DHA)4c7c10c13c16c19c-22:6 (n-3) 9,12,15,18,21-tetracosapentaenoic —9c12c15c18c21c-24:5 (n-3) tetracosahexaenoic nisinic6c9c12c15c18c21c-24:6 (n-3) Omega-6 Fatty Acids octadecadienoic linoleic9c12c-18:2 (n-6) octadecatrienoic γ-linolenic (GLA) 6c9c12c-18:3 (n-6)11,14-eicosadienoic — 11c14c-20:2 (n-6) eicosatrienoicdihomo-γ-linolenic (DGLA) 8c11c14c-20:3 (n-6) eicosatetraenoicarachidonic (AA) 5c8c11c14c-20:4 (n-6) 13,16-docosadienoic — 13c16c-22:2(n-6) docosatetraenoic adrenic 7c10c13c16c-22:4 (n-6) docosapentaenoicosbond 4c7c10c13c16c-22:5 (n-6) Omega-9 Fatty Acids eicosatrienoic meadacid 5c8c11c-20:3 (n-9) Conjugate Linoleic Acids (CLA) octadecadienoicrumenic 9c11t-18:2 (n-7) octadecadienoic CLA 10t12c-18:2 (n-6)Conjugated Linolenic Acids octadecatrienoic α-calendic 8t10t12c-18:3(n-6) octadecatrienoic β-calendic 8t10t12t-18:3 (n-6) octadecatrienoicjacaric 8t10c12t-18:3 (n-6) octadecatrienoic α-eleostearic 9c11t13t-18:3(n-5) octadecatrienoic β-eleostearic 9t11t13t-18:3 (n-5)octadecatrienoic catalpic 9c11c13t-18:3 (n-5) octadecatrienoic punicic9c11t13c-18:3 (n-5) Other Conjugated Polyenoic Fatty Acidsoctadecatrienoic rumelenic 9t11c16t-18:3 (n-3) octadecatetraenoicα-parinaric 9t11c13c15t-18:4 (n-3) octadecatetraenoic β-parinaric9t11t13t15t-18:4 (n-3) eicosapentaenoic bosseopentaenoic5c8c10t12t14c-20:5 (n-6) octadecadienoic laballenic 5e6e-18:2 (n-12)

TABLE IV Acetylenic fatty acids Systematic Name Trivial Name ShorthandDesignation Monoacetylenic Fatty Acids octadecynoic stearolic 9y-18:0octadecynoic tariric 6y-18:0 octadecenynoic santalbic 9y11t-18:1 (n-7)6,9-octadecenynoic — 6e9y-18:1 (n-12) heptadecenynoic pyrulic 8y10t-17:1(n-7) octadecenynoic crepenynic 9c12y-18:1 (n-8) heptadecenynoicscleropyric 12y16e-17:1 (n-1) Polyacetylenic Fatty Acidstridecatetraenediynoic mycomycin 3e5e7e8e10y12y-13:4 (n-5)tridecadienetriynoic isomycomycin 3e5e7y9y11y-13:2 (n-8)octadecadienediynoic dihydrooropheic 9y11y13e17e-18:2 (n-1)heptadecadienediynoic phomallenic acid B 8e9e11y13y-17:2 (n-8)octadecadienediynoic phomallenic acid C 9e10e12y14y-18:2 (n-8)octadecenediynoic exocarpic 9y11y13c-18:1 (n-5) octadecenetriynoicoropheic 9y11y13y17e-18:1 (n-1)

TABLE V Substituted fatty acids Systematic Name Trivial Name ShorthandDesignation Alkyl-Substituted Fatty Acids methylpropanoic isoutyric2m-4:0 methylhexadecanoic anteisoheptadecanoic 14m-16:08-methyl-6-nonenoic — 6t8m-9:1 (n-3) methyloctadecanoic tuberculostearic10m-18:0 methyloctadecanoic anteisononadecanoic 16m-18:0trimethyloctacosanoic mycoceranic 2m4m6m-28:0 trimethyltetracosenoicmycolipenic 2m2t4m6m-24:1 (n-22) heptamethyltriacontanoic phthioceranic2m4m6m8m10m12m14-30:0 tetramethylhexadecanoic phytanic 3m7m11m15m-16:0tetramethylpentadecanoic pristanic 2m6m10m14m-15:0 Hydroxy-SubstitutedFatty Acids Monohydroxy Fatty Acids hydroxyoctadecatrienoic2-hydroxylinolenic 2h9c12c15c-18:3 (n-3) hydroxyoctadecenoic2-hydroxyoleic 2h9c-18:1 (n-9) hydroxytetracosanoic cerebronic 2h-24:0hydroxytetracosenoic hydroxynervonic 2h15e-24:1 (n-9) 3-hydroxybutyric —3h-4:0 hydroxyoctadecadienediynoic isanolic 8h9y11y17e-18:1 (n-2)hydroxyoctadecenoic strophanthus 9h12c-18:1 (n-7) hydroxyoctadecadienoicβ-dimorphecolic 9h10t12t-18:2 (n-7) 10-hydroxydecanoic — 10h-10:0hydroxydecenoic royal jelly acid 2t10h-10:1 (n-8) hydroxyoctadecenoicRicinoleic 9c12h-18:1 (n-9) hydroxyoctadecadienoic Densipolic9c12h15c-18:2 (n-4) hydroxyoctadecadienoic Coriolic 9c11t13h-18:2 (n-8)hydroxyeicosenoic Lesquerolic 11e14h-20:1 (n-10) hydroxyeicosadienoicAuricolic 11e14h17e-20:2 (n-4) hydroxyhexadecanoic juniperic 16h-16:0hydroxyoctadecatrienoic kamlolenic 9c1t13t18h-18:3 (n-5) PolyhydroxyFatty Acids dihydroxytetracosenoic axillarenic 9e11h13h-24:1 (n-16)dihydroxydocosanoic byrsonic 3h7h-22:0 hydroxydocosanoic phellonic22h-22:0 trihydroxyoctadecanoic phloionolic 9h10h18h-8:0trihydroxyhexadecanoic aleuritic 9h10h16h-16:0 trihydroxyicosahexaenoicresolvin D1 4c7h8h9t11t13c15t17h19c-20:5 (n-4) trihydroxyicosapentaenoicresolvin E1 5h6t8t10t12h14c16t-20:5 (n-4) Carboxy-Substituted FattyAcids ethanedioic oxalic 1,2dioic-2:0 propanedioic malonic 1,3dioic-3:0butanedioic succinic 1,4dioic-4:0 pentanedioic glutaric 1,5dioic-5:0hexanedioic adipic 1,6dioic-6:0 heptanedioic pimelic 1,7dioic-7:0octanedioic suberic 1,8dioic-8:0 nonanedioic azelaic 1,9dioic-9:0decanedioic sebacic 1,10dioic-10:0 tridecanedioic brassylic1,13dioic-13:0 ethanedioic oxalic 1,2dioic-2:0 propanedioic malonic1,3dioic-3:0 hexadecanedioic thapsic 1,16dioic-16:0methylidenebutanedioic itaconic 2Md1,4dioic-4:0 methylbutenedioicmesaconic 2m2t1,4dioic-4:1 (n-2) dodecenedioic traumatic1,12dioic2t-12:1 (n-10) dimethyltriacontanedioic diabolic 1,30dioic15m16m-30:0 tetramethyl- crocetin 1,16dioic2m2t4t6m6t8t10thexadecaheptaenedioic 11m12t14t15m-16:7 (n-2)methyltetradecyl-butenedioic chaetomellic acid A 2m2c3a1,4dioic; a =—C₁₄H₂₉-4:1 (n-2) methylidene- ceriporic acid A 2Md3a1,4dioic;tetradecylbutanedioic a = —C₁₄H₂₉-4:0 Sulfate-Substituted Fatty Acidsdisulfooxyhexadecanoic caeliferin A16:0 2Sul16Sul-16:0disulfooxyhexadecenoic caeliferin A16:1 2Sul6t16Sul-16:1 (n-10)Methoxy-Substituted Fatty Acids 2-methoxy-5-hexadecenoic — 2OMe5e-6:1(n-1) 2-methoxy hexadecanoic 2OMe-16:0 7-methoxy-4-tetradecenoic —4e7OMe-14:1 (n-10) 9-methoxypentadecanoic — 9OMe-9:011-methoxyheptadecanoic — 11OMe-17:0 3-methoxydocosanoic — 3OMe-22:0Acetoxy-Substituted Fatty Acids diacetoxydocosanoic byrsonic3OAc7OAc-22:0 2-acetoxydocosanoic — 2OAc-22:0 2-acetoxytetracosanoic —2OAc-24:0 2-acetoxyhexacosanoic — 2OAc-26:0 Aldehyde-Substituted FattyAcids 9-oxononanoic — 9o-9:0 oxodecanoic traumatin 12o-12:0oxododecenoic traumatin 9e12o-12:1 (n-3) hydroxyoxodecenoichydroxytraumatin 9h10e12o-12:1 (n-2) 10-oxo-8-decenoic — 8t10o-10:1(n-2) 13-oxo-9,11-tridecadienoic — 9c11t13o-13:2 (n-2) Halogenated FattyAcids Fluoro-Substituted Fatty Acids fluorooctadecenoic ω-fluorooleic9e18F-18:1 (n-9) fluorodecanoic ω-fluorocapric 10F-10:0fluorotetradecanoic ω-fluoromyristic 14F-14:0 fluorohexadecanoicω-fluoropalmitic 16F-16:0 fluorooctadecadienoic ω-fluorolinoeic9c12c18F-18:2 (n-6) Chloro-Substituted Fatty Acidschlorohydroxyhexadecanoic 9-chloro-10-hydroxypalmitic 9Cl10h-16:0chlorohydroxyhexadecanoic 10-chloro-9-hydroxypalmitic 10Cl9h-16:0chlorohydroxyoctadecanoic 9-chloro-10-hydroxystearic 9Cl10h-18:0chlorohydroxyoctadecanoic 11-chloro-12-hydroxystearic 11Cl12h-18:0dichlorooctadecanoic 9,10-dichlorostearic 9Cl10Cl-18:0 Bromo-SubstitutedFatty Acids 3-bromo-2-nonaenoic — 2e3Br-9:1 (n-7)9,10-dibromooctadecanoic — 9Br10Br-18:0 9,10,12,13- —9Br10Br12Br13Br-18:0 tetrabromooctadecanoic Nitro-Substituted FattyAcids 10-nitro-9,12- 10-nitrolinoleic 9c10Nitro12c-18:2 (n-6)octadecadienoic 12-nitro-9,12- 12-nitrolinoleic 9c12c12Nitro-18:2 (n-6)octadecadienoic 9-nitro-9-octadecenoic 9-nitrooleic 9c9Nitro-18:1 (n-9)Keto-Substituted Fatty Acids 9-oxo-2-decenoic 9-ODA 2t9k-10:1 (n-8)9-oxo-13-octadecenoic — 9k13e-18:1 (n-5) oxooctadecatrienoic licanic4k9c11t13t-18:3 (n-5) 15-oxo-18-tetracosenoic — 15k18e-28:1 (n-6)17-oxo-20-hexacosenoic — 17k20e-26:1 (n-6) 19-oxo-22-octacosenoic —19k22e-28:1 (n-6) 9-hydroxy-10-oxo-12,15- — 9h10k12t15t-18:2 (n-3)octadecadienoic

TABLE VI Heteroatom containing fatty acids Systematic name Trivial nameFormula Carbon Chain with Divinyl Ether Function 9-(1,3-nonadienoxy)-8-colnelenic CH₃(CH₂)₄CH═CHCH═CH—O—CH═CH(CH₂)₆CO₂H nonenoic9-(1,3,6-nonatrienoxy)-8- colnelenicCH₃CH₂CH═CHCH₂CH═CHCH═CH—O—CH═CH(CH₂)₆CO₂H nonenoic12-(1-hexenoxy)-9,11- etheroleic CH₃(CH₂)₃CH═CH—O—CH═CHCH═CH(CH₂)₇CO₂Hdodecadienoic 12-(1,3-hexadienoxy)-9,11- etherolenicCH₃CH₂CH═CHCH═CH-O—CH═CHCH═CH(CH₂)₇CO₂H dodecadienoic Sulfur-ContainingCarbon Chain 2-dodecylsulfanylacetic dodecylthioaceticCH₃(CH₂)₁₁—S—CH₂CO₂H 2-tetradecylsulfanylacetic tetradecylthioaceticCH₃(CH₂)₁₃—S—CH₂CO₂H (TTA) 3-tetradecylsulfanylprop-2-tetradecylthioacrylic CH₃(CH₂)₁₃—S—CH═CHCO₂H enoic (TTAcr)3-tetradecylsulfanylpropanoic tetradecylthiopropionicCH₃(CH₂)₁₃—S—(CH₂)₂CO₂H (TTP)

TABLE VII Ring containing fatty acids Systematic Name Trivial NameShorthand Designation Fatty Acids with 3-Membered Rings CyclopropaneFatty Acids 10-(2- lactobacillic 11-12m:18:0 hexylcyclopropyl)decanoic8-(2-octylcyclopropyl)octanoic — 9-10m:18:08-(2-hexylcyclopropyl)octanoic — 9-10m-16:0 3-(2-[6-bromo-3,5-nondienylcyclopropyl) propanoic majusculoic

9-(2- amphimic 5c9t10-11m-27:2 (n-18) hexadecylcyclopropylidene) acid Anon-5-enoic Cyclopropene Fatty Acids 8-(2-octyl-1- sterculic9e9-10m-18:1 (n-9) cyclopropenyl)octanoic 7-(2-octyl-1- malvalic8e8-9m-17:1 (n-9) cyclopropenyl)heptanoic Epoxy Fatty Acids9,10-epoxyoctadecenoic 9,10- 9-10epoxy-18:0 epoxystearic9,10-epoxy12-octadecanoic coronaric 9-10epoxy12e-18:1 (n-6)12,13-epoxy-9-octadecenoic vernolic 9e12-13epoxy-18:1 (n-9)14,15-epoxy-11-eicosenoic alchornic 11e14-15epoxy-20:1 (n-9)8-hydroxy-11,12-epoxy-5,9,14- hepoxilin A3 5t8h9t11-12epoxy14t-20:3(n-6) eicosatrienoic Fatty Acids with 5-Membered Rings11-(2-cyclopenten-1- yl)undecanoic hydnocarpic

13-(2-cyclopenten-1- yl)tridecanoic chaulmoogric

13-(2-cyclopentenyl)-6- tridecenoic gorlic

9-(2-(but-1- enyl)cyclopentyl)nonanoic —

3-methyl-6-(3-(6-methylheptan- 2-yl)-cyclopentyl)hexanoic

2-(3′-(6-methylheptan-2-yl)- bi(cyclopentan)-3-yl)acetic

Fatty Acids with 6-Membered Rings 11-cyclohexylundecanoic —

13-cyclohexyltridecanoic —

9-(6-(prop-1-enyl)cyclohex-3- enyl)-nonanoic —

8-(6-(3-pentenyl)-3- cyclohexenyl)-5,7-octadienoic —

Furan Containing Fatty Acids 7-(3,4-dimethyl-5-pentylfuran-2-yl)heptanoic —

9-(4-methyl-5-pentylfuran-2- yl)nonanoic —

11-(3,4-dimethyl-5-pentylfuran- 2-yl)undecanoic —

11-(4-methyl-5-pentylfuran-2- yl)undecanoic —

2-(2-carboxyethyl)-4-methyl-5- propylfuran-3-carboxylic —

3,3′-(3,4-dimethylfuran-2,5- diyl)dipropanoic —

Ladderane Containing Fatty Acids 4-[5]-ladderane-butanoic —

6-[5]-ladderane-hexanoic —

8-[5]-ladderane-octanoic —

6-[3]-ladderane-hexanoic —

In one embodiment, the fatty acid conjugated to quetiapine, its activemetabolite or derivative used in the compositions, systems and methodsdescribed herein, is any one of the fatty acids in Tables I-VII providedherein, or a combination thereof. Accordingly and in one embodiment,provided herein is a composition for treating a psychiatric disorder ina subject, comprising a conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine) and at least one saturated fatty acid. In anotherembodiment, quetiapine is conjugated to at least one monounsaturatedfatty acid, or a polyunsaturated fatty acid in another embodiment, or anacetylenic fatty acid, a substituted fatty acid, a heteroatom containingfatty acid, a ring containing fatty acid; a salt thereof, a derivativethereof or their combination in other, discrete embodiments of theconjugates of quetiapine provided herein.

In another embodiment, the fatty acid conjugated to quetiapine or itsactive metabolite, used in the compositions and methods describedherein, is a saturated fatty acid such as palmitic acid in oneembodiment, a monounsaturated fatty acid such as palmitoleic acid inanother embodiment, a polyunsaturated fatty acid such as DHA in yetanother discrete embodiment of the fatty acid conjugated to quetiapineaccording to the invention.

In one embodiment, the active metabolite of quetiapine isN-desalkyl-quetiapine (nor QTP).

nor QTP is a major active human plasma metabolite of quetiapine, whichhas shown in-vitro antagonistic activity on multiple brainneurotransmitter receptors and in particular on serotonergic(5-HT_(2A)), adrenergic (α₁-adrenoreceptor) and the noradrenergictransporter, thus having in another embodiment, a positive influence onmood. Likewise, N-desalkyl-quetiapine, has a high affinity for thehistamine H₁ receptor and moderate affinities for the norepinephrinereuptake transporter (NET), the serotonin 5-HT_(1A), 5-HT_(1E),5-HT_(2A), 5-HT_(2B), 5-HT₇ receptors, the α_(1B)-adrenergic receptor,and the M₁, M₃, and M₅ muscarinic receptors. In one embodiment,N-desalkyl-quetiapine has about 100-fold higher avidity for inhibitinghuman NET than quetiapine itself. Additionally, N-desalkyl-quetiapine is10-fold more potent and more efficacious than quetiapine at the5-HT_(1A) receptor. N-Desalkyl-quetiapine is an antagonist at 5-HT_(2A),5-HT_(2B), 5-HT_(2c), α_(1A), α_(1D), α_(2A), α_(2C), H₁, M₁, M₃, and M₅receptors, with a moderate affinity for the norepinephrine reuptakeinhibitor transporter (NET) and partial 5-HT1_(A) agonism, indicating asignificant antidepressant effects. In one embodiment, the compositionsprovided herein, which in another embodiment are used in the methodsprovided herein comprise the N-desalkyl-quetiapine, conjugated to asaturated fatty acid such as valproate, or a monounsaturated fatty acid,a polyunsaturated fatty acid, an acetylenic fatty acid, a substitutedfatty acid, a heteroatom containing fatty acid, a ring containing fattyacid or a combination thereof, each a discrete embodiment of the fattyacid conjugates without the presence of quetiapine.

In one embodiment, the active metabolite of quetiapine is7-hydroxy-quetiapine (7-OH-QTP).

7-OH-QTP is another active human plasma metabolite of quetiapine havingintrinsic receptor activity. 7-hydroxy-quetiapine has been shown tooccupy dopamine D₂ and serotonin 5-HT₂ receptors. In one embodiment, thecompositions provided herein, which in another embodiment is used in themethods provided herein comprise 7-hydroxy-quetiapine, conjugated to asaturated fatty acid, or a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid or acombination thereof, each a discrete embodiment of the fatty acidconjugated to 7-OH-QTP, without the presence of quetiapine.

In another embodiment, the term “derivative” refers to having asubstituent bonded to quetiapine or its active metabolite such ashalogenated derivatives ether derivatives, acid derivatives, amidederivatives, ester derivatives and the like. Methods of preparingderivatives such as ether derivatives in one embodiment comprisecoupling of the corresponding alcohols. In another embodiment, the term“derivative” refers to a chemical compound related structurally toquetiapine or its active metabolites and is therapeutically derivablefrom it. In one embodiment, the term “active derivative” refers to aderivative as defined herein, which is accountable for a desiredbiological effect. Accordingly, an active derivative of quetiapine willhave in one embodiment an antipsychotic activity, or an antidepressantactivity and the like in other embodiments of desired biologicaleffects.

In one embodiment, the active derivative of quetiapine is2-chloro-N-desalkyl-quetiapine (2-Cl-nor QTP).

2-Cl-nor QTP a derivative of nor QTP, which, due to its similarstructure to the known antidepressant amoxapine, is thought to possesssimilar psychiatric activity as a norepinephrine reuptake inhibitorand/or as a partial 5-HT agonist. In one embodiment, the compositionsprovided herein, which in another embodiment is used in the methodsprovided herein comprise 2-chloro-N-desalkyl-quetiapine, conjugated to asaturated fatty acid, a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid and/orits pharmaceutically acceptable salt, without the presence ofquetiapine; and/or active metabolites thereof.

In one embodiment, using 2-Cl-nor QTP conjugated to a saturated fattyacid, or a monounsaturated fatty acid, a polyunsaturated fatty acid, anacetylenic fatty acid, a substituted fatty acid, a heteroatom containingfatty acid, a ring containing fatty acid or a combination thereof, eacha discrete embodiment of the fatty acid conjugated to 2-Cl-nor QTP; doesnot lower the seizure threshold to the extent that fits may beprecipitated in chronic administration, especially in children.

In one embodiment, the active derivative of quetiapine is7-hydroxy-N-desalkylquetiapine (7-OH-nor QTP).

7-OH-nor QTP a derivative of nor QTP, which, due to its similarstructure to the known active quetiapine metabolite7-hydroxy-quetiapine, is thought to possess similar activities. In oneembodiment, the compositions provided herein, which in anotherembodiment is used in the methods and transdermal systems providedherein comprise 7-hydroxy-N-desalkyl-quetiapine, conjugated to asaturated fatty acid, or a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid or acombination thereof and/or its pharmaceutically acceptable salt, each adiscrete embodiment of the 7-OH-nor QTP conjugates provided herein,without the presence of quetiapine; and/or active metabolites thereof.

In one embodiment, the fatty acid is acetic acid and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylacetate,2(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylacetate, 1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethanone,1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethanone;their derivative, pharmaceutically acceptable salt or their combination.

In one embodiment, the fatty acid is butyric acid and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylbutyrate,2(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylbutyrate,1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)butan-1-one,1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)butan-1-one;their derivative, pharmaceutically acceptable salt or their combination.

In another embodiment, the fatty acid is valeric acid, and the conjugateis 2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylvalerate,2(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylvalerate,1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)pentan-1-one,1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)pentan-1-one;their derivative, pharmaceutically acceptable salt or their combination.

In one embodiment, the fatty acid is caprylic acid and the conjugate is2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylcaprylate,2-(2-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethylcaprylate,1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)octan-1-one,1-(4-(7-hydroxydibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)octan-1-one;their derivative, pharmaceutically acceptable salt or their combination.

In one embodiment, the saturated fatty acid conjugated to quetiapine,its active metabolite and/or active derivative, their pharmaceuticallyacceptable salt and/or their combination is any one of the fatty acidsprovided in Table I herein. In another aspect, the monounsaturated fattyacid conjugated to quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination is selected from the group consisting of any one of thefatty acids set forth in Table II. In another aspect, thepolyunsaturated fatty acid conjugated to quetiapine, its activemetabolite and/or active derivative, their pharmaceutically acceptablesalt and/or their combination is selected from the group consisting ofany one of the fatty acids set forth in Table III. In one embodiment,the acetylenic fatty acid conjugated to quetiapine, its activemetabolite and/or active derivative, their pharmaceutically acceptablesalt and/or their combination is selected from the group consisting ofany one of the fatty acids set forth in Table IV.

In one embodiment, the substituted fatty acid conjugated to quetiapine,its active metabolite and/or active derivative, their pharmaceuticallyacceptable salt and/or their combination is an alkyl-substituted fattyacid. In another embodiment, the substituted fatty acid conjugated toquetiapine, its active metabolite and/or active derivative, theirpharmaceutically acceptable salt and/or their combination is ahydroxy-substituted fatty acid, carboxy-substituted fatty acid,halogenated fatty acid, sulfate-substituted fatty acid,methoxy-substituted fatty acid, acetoxy-substituted fatty acid,aldehyde-substituted fatty acid, nitro-substituted fatty acid, orketo-substituted fatty acid, each a discrete embodiment of thesubstituted fatty acid conjugated to quetiapine, its active metaboliteand/or active derivative, their pharmaceutically acceptable salt and/ortheir combination. In another aspect, the substituted fatty acidconjugated to quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination is selected from the group consisting of any one of thefatty acid compounds set forth in Table V.

In one embodiment, the heteroatom containing fatty acid conjugated toquetiapine, its active metabolite and/or active derivative, theirpharmaceutically acceptable salt and/or their combination has a carbonchain containing a divinyl ether function. In another embodiment, theheteroatom containing fatty acid conjugated to quetiapine, its activemetabolite and/or active derivative, their pharmaceutically acceptablesalt and/or their combination has a carbon chain containing a sulfurfunction. In another aspect, the heteroatom containing fatty acidconjugated to quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination, is selected from the group consisting of any one of thefatty acid compounds set forth in Table VI.

In one embodiment, the ring containing fatty acid conjugated toquetiapine, its active metabolite and/or active derivative, theirpharmaceutically acceptable salt and/or their combination is a fattyacid containing at least one three-membered ring, a fatty acidcontaining at least one five-membered ring, a fatty acid containing atleast one six-membered ring, a fatty acid containing ladderanes, a fattyacid containing at least one furan ring or a combination thereof, each adiscrete embodiment of the ring containing fatty acid conjugated toquetiapine, its active metabolite and/or active derivative, theirpharmaceutically acceptable salt and/or their combination. In anotheraspect, the ring containing fatty acid conjugated to quetiapine, itsactive metabolite and/or active derivative, their pharmaceuticallyacceptable salt and/or their combination, is selected from the groupconsisting of any one of the fatty acid compounds set forth in TableVII.

Fatty acid ester prodrugs of quetiapine as described above can beadministered orally and the active drug is released after hydrolysis inthe body. In one embodiment, these prodrugs are easily recognized byphysiological systems because the attached fatty acid moieties areeither naturally occurring or mimic naturally occurring compounds. As aresult, the prodrugs provided herein are hydrolyzed chemically,enzymatically or by a combination of chemical and enzymatic processes;and release quetiapine. In another embodiment the compositionscomprising the prodrugs described herein, are either pharmacologicallyinactive, have pharmacological activity that is limited or differentfrom the parent drug, and consequently, in certain embodiments, mayfollow a metabolic pathway that differs from quetiapine. In anotheraspects, both quetiapine and the fatty acid are therapeutically activein the subject In another embodiment, the term “prodrug” refers to aprecursor or derivative form of a pharmaceutically active substance thatimparts higher bioavailability to quetiapine compared to the parent drugand is capable of being enzymatically or hydrolytically activated orconverted into the more active parent form. In one embodiment, thecompositions comprising the prodrugs described herein would releasequetiapine in a similar fashion to free or unconjugated quetiapine. Inanother embodiment, the compositions comprising the prodrugs describedherein would release quetiapine in a controlled or sustained mannerwithout the need of an extended release formulation. In another aspect,sustained or controlled release is obtained by conjugating quetiapine asdescribed herein to a functionalized fatty acid capable of beingcross-linked, whereby the degree of cross-linking affect the rate ofrelease of quetiapine, its active metabolite and/or active derivative,by affecting the diffusion rate of the enzyme or chemical agentaffecting the hydrolysis of the conjugate in one embodiment.

In a further embodiment, the compositions comprising the prodrugsdescribed herein would have increased absorption over unmodifiedquetiapine. In another embodiment, the increased absorption overunmodified quetiapine, or improved water solubility over freequetiapine, provide for a better bioavailability of quetiapine referringto a higher AUC or higher circulating plasma concentrations.

In yet another embodiment, the compositions comprising the prodrugsdescribed herein would have increased bioavailability over unconjugatedquetiapine. This may allow for administration of a lower dose with equalor improved therapeutic effect, but with fewer and/or less severeside-effects when compared to unmodified quetiapine, thereby improvingthe safety profile of the drug. Common adverse side-effects associatedwith quetiapine include sedation, constipation, dizziness, dry mouth,lightheadedness, nasal congestion, sore throat, stomach pain or upset,tiredness, vomiting, weakness, weight gain, hyperlipidemia, hypotension,hyperglycemia and more. In one embodiment, the use of the compositionsdescribed herein results in elimination, amelioration, reduction orimprovement in common side-effects associated with chronic or acuteadministration of quetiapine.

In another embodiment, the compositions comprising the prodrugsdescribed herein would reduce weight gain when compared to unconjugatedquetiapine. Accordingly and in one embodiment, the invention provides amethod of reducing weight gain resulting from chronic or acuteadministration of quetiapine in a subject, comprising the step oforally, transdermally or rectally administering to the subject acomposition comprising a therapeutically effective amount of about1-2000 mg/dose based on equimolar weight of unconjugated quetiapine; ofquetiapine or its active metabolite and/or active derivative thereofsuch as 7-hydroxy-N-desalkyl-quetiapine, or 7-hydroxy-quetiapine,conjugated to a saturated fatty acid, a monounsaturated fatty acid, apolyunsaturated fatty acid, an acetylenic fatty acid, a substitutedfatty acid, a heteroatom containing fatty acid, a ring containing fattyacid, a pharmaceutically acceptable salt thereof, or derivative thereof,or their combination, thereby modulating leptin and/or ghrelin levels,or in another embodiment, altering the metabolism of quetiapine, itsmetabolite(s) and/or derivative(s), resulting in reduced binding tohistamine receptor(s) in the subject and thereby eliminating, reducing,delaying, decreasing and/or inhibiting weight gain in the subject.

In one embodiment, chronic oral administration of quetiapine, a knownorexigenic, for a period of 6 weeks causes about 37% increase in leptinrelease. In another aspect, conjugating an active metabolite and/orderivative of quetiapine to a saturated fatty acid, a monounsaturatedfatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, a ringcontaining fatty acid or a combination thereof, will modulate therelease of leptin and/or ghrelin, resulting in certain embodiments withlower weight gain or lower increase in body/mass index (BMI). Sinceghrelin regulates the release of leptin in certain embodiments, and isreleased in response to fasting and cachexia, ingestion of at least onefatty acid conjugate of quetiapine as set forth in Tables I-VII, willdecrease its release, resulting in lower weight gain.

In another embodiment, the compositions comprising the conjugatesdescribed herein would generate a C_(max) value of released quetiapinethat is higher than the C_(max) value produced by unconjugatedquetiapine when administered at equimolar doses (See e.g., FIG. 1). In afurther embodiment, the compositions comprising the prodrugs describedherein would generate an AUC value of released quetiapine that is higherthan the AUC value produced by unconjugated quetiapine when administeredat equimolar doses. In yet another aspect, the compositions comprisingthe prodrugs described herein would generate both a C_(max) and an AUCvalue of released quetiapine that is higher than the C_(max) and AUCvalues produced by unconjugated quetiapine when administered atequimolar doses.

In another embodiment the compositions comprising the conjugatesdescribed herein would generate a T_(max) value of released quetiapinethat is longer than the T_(max) value produced by unconjugatedquetiapine when administered at equimolar doses. In another embodimentthe compositions comprising the prodrugs described herein would generatea T_(max) value of released quetiapine that is similar to the T_(max)value produced by unconjugated quetiapine, when administered atequimolar doses.

In another embodiment, the compositions comprising the prodrugsdescribed herein would have reduced interindividual variability eitherdue to increased bioavailability in one aspect, or due to a modifiedmetabolic pathway in another aspect, or due to a combination of both inyet another aspect.

In another embodiment, the compositions comprising the prodrugsdescribed herein would alter the metabolic pathway of the releasedquetiapine when compared to unmodified quetiapine. This new metabolismmay decrease interindividual variability and/or reduce side-effectsassociated with unconjugated quetiapine or any of its metabolites,pharmaceutically acceptable salts, derivatives thereof or theircombination.

In yet another embodiment, the compositions comprising the prodrugsdescribed herein would decrease the number and/or amount ofmetabolites—active, inactive, toxic or non-toxic—produced by unmodifiedquetiapine. This may decrease interindividual variability and/or reduceside-effects associated with the administration of unconjugatedquetiapine.

In a further embodiment, the compositions comprising the prodrugsdescribed herein would increase the amount of active metabolites whencompared to unmodified quetiapine. This may improve the therapeuticefficacy of the parent drug.

Although quetiapine is not a controlled substance, there have beenincreasing reports of its misuse via oral, intranasal, and intravenousroutes to exploit its potent sedative and anxiolytic properties. Some ofits street names include “quell”, “baby heroin” and “Susie-Q”. In someembodiments, the compositions comprising the prodrugs described hereinmay not be hydrolyzed efficiently when administered by non-oral routes.As a result, these prodrugs may generate plasma concentrations ofreleased quetiapine that are lower when compared to free quetiapineadministered intravenously (“injected”) or intranasally (“snorted”).Accordingly, by altering the metabolic pathway the conjugated compoundsprovided herein may decrease the potential for abuse of quetiapine.

In one embodiment provided herein, quetiapine or its active metabolite,is conjugated to at least one fatty acid as represented by any one ofthe structures of formulas I-IV:

a pharmaceutically acceptable salt thereof, a derivative thereof or acombination thereof, wherein “R” is a fatty acid side-chain selectedfrom the group consisting at least one of the fatty acids set forth inTables I-VII.

In one embodiment, the salt of the conjugate of quetiapine or an activemetabolite and/or derivative thereof and a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid or a combination thereof, such as anyone of the structures represented by formulas I-IV hereinabove, and thefatty acid represented by any of the compounds in Tables I-VII, is anacetate salt. In another aspect, the salt of the conjugate of quetiapineor an active metabolite and/or derivative thereof and a saturated fattyacid, a monounsaturated fatty acid, a polyunsaturated fatty acid, anacetylenic fatty acid, a substituted fatty acid, a heteroatom containingfatty acid, a ring containing fatty acid or a combination thereof isL-aspartate, or besylate, bicarbonate, carbonate, D-camsylate,L-camsylate, citrate, edisylate, formate, fumarate, gluconate,hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate,D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate,succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate,meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate,isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate,orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate,aminosalicylate, ascorbate, borate, butyrate, camphorate,camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutamate,glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate,hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate,maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate,oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate,salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate,thiosalicylate, tribrophenate, valerate, valproate, adipate,4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate,thiocyanate, and undecylenate or a mixture thereof, in other discreteembodiments of the salts of the conjugate of quetiapine or an activemetabolite and/or derivative thereof and a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid or a combination thereof comprisingthe compositions and used in the methods and systems provided herein.

Formulation Examples

In one embodiment, the composition comprising the conjugate ofquetiapine or an active metabolite and/or derivative thereof and asaturated fatty acid, a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid or acombination thereof is formulated for oral administration. In anotheraspect, the composition comprising the conjugate of quetiapine or anactive metabolite and/or derivative thereof and a saturated fatty acid,a monounsaturated fatty acid, a polyunsaturated fatty acid, anacetylenic fatty acid, a substituted fatty acid, a heteroatom containingfatty acid, a ring containing fatty acid or a combination thereof isformulated for sublingual, or transdermal, intrathecal or a suppositoryadministration in other discrete formulation embodiments of thecompositions provided herein and are used in the systems and methodsdescribed herein.

In one embodiment, the term “intrathecal administration” refers to thedelivery of an active compound formulation directly into thecerebrospinal fluid of a subject, by lateral cerebroventricularinjection through a burr hole or cistemal or lumbar puncture or the like(described in Lazorthes et al., 1991, and Ommaya A. K., 1984, thecontents of which are incorporated herein by reference in its entirety).The term “lumbar region” refers to the area between the third and fourthlumbar (lower back) vertebrae. The term “cistema magna” refers to thearea where the skull ends and the spinal cord begins at the back of thehead. The term “cerebral ventricle” refers to the cavities in the brainthat are continuous with the central canal of the spinal cord.Administration of quetiapine, its active metabolite(s) and/orderivative(s) conjugated to a saturated fatty acid such as valproicacid, a monounsaturated fatty acid, a polyunsaturated fatty acid such asDHA and/or EPA, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid or acombination thereof to any of the above mentioned sites can be achievedby direct injection of the active compound formulation or by the use ofinfusion pumps. Implantable or external pumps and catheter may be used.

The prodrugs provided in the compositions and methods herein are gearedin one embodiment, towards oral dosage forms. These dosage forms includebut are not limited to a tablet, capsule, caplet, pill, powder, troche,lozenge, slurry, liquid solution, suspension, emulsion, elixir or oralthin film (OTF), each a discrete aspect of the oral dosage form used inthe compositions and methods provided herein. Preferred oraladministration forms are capsule in one embodiment, or tablet, solutionsand OTF in certain other embodiments. The film dosage forms provide aninexpensive, convenient and immediate method for delivery of thecompositions described herein without the undesirable aspects associatedwith certain oral or nasal delivery methods, while providingversatility, safety and patient comfort. Any effective edible “thinfilm” or “strip” may be used in accordance with the present invention.Unless otherwise specified or required by the context, the edible filmsof the present invention may be manufactured in any effective manner.

In certain aspects, the film layer can be produced using a highlywater-soluble polymer comprising a natural or synthetic water-solublepolymer. The polymer preferably has good film moldability, produces asoft flexible film, and is safe for human consumption. In anotherembodiment, one such polymer can be a water-soluble cellulose derivativelike hydroxypropyl cellulose (HPC), methyl cellulose, hydroxypropylalkylcellulose, carboxymethyl cellulose or the salt of carboxymethylcellulose. Or, the polymer can comprise an acrylic acid copolymer or itssodium, potassium or ammonium salt. The acrylic acid copolymer or itssalt can be combined with methacrylic acid, styrene or a vinyl type ofether as a comonomer, polyvinyl alcohol, polyvinylpyrrolidone,polyalkylene glycol, hydroxypropyl starch, alginic acid or its salt,polysaccharide or its derivatives such as tragacanth, gum gelatin,collagen, denatured gelatin, and collagen treated with succinic acid oranhydrous phthalic acid. In another embodiment the powder matrix maycomprise as adhesives: poorly water-soluble cellulose derivativesincluding ethyl cellulose, cellulose acetate and butyl cellulose;shellac; higher fatty acids including stearic acid and palmitic acid.The following can also, without limitation, be used to produce the filmlayer: pullulan, maltodextrin, pectin, alginates, carrageenan, guar gum,other gelatins, etc. The thickness of the film layer can vary asdesired, but typically is in the range of 0.01 mm to 3.00 mm, preferably0.03 mm to 1.00 mm. In one embodiment, the saturated fatty acid, ormonounsaturated fatty acid, polyunsaturated fatty acid, acetylenic fattyacid, substituted fatty acid, heteroatom containing fatty acid, ringcontaining fatty acid or their combination in other discrete embodimentsthat are used in the conjugate of quetiapine or an active metaboliteand/or derivative thereof provided herein will be affected by thecomposition of the OTF.

Solid dosage forms can include the following types of excipients:antiadherents, binders, coatings, disintegrants, fillers, flavors andcolors, glidants, lubricants, preservatives, sorbents and sweeteners.

For oral administration, the conjugates can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the conjugates providedherein to be formulated as tablets, pills, dragées, capsules, liquids,gels, syrups, slurries, suspensions, and the like, for oral ingestion bya patient. Pharmacological preparations for oral use can be made using asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries ifdesired, to obtain tablets or dragée cores. Suitable excipients are, incertain embodiments, fillers such as sugars, including lactose, sucrose,manioc, or sorbitol; cellulose preparations such as, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodiumcarboxymethyl cellulose and/or physiologically acceptable polymers suchas polyvinylpyrrolidone (PVP). If desired, in certain embodimentsdisintegrating agents may be added, such as cross-linkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate.

Dragée cores may be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragée coatings for identification or to characterizedifferent combinations of active compound doses.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile, pyrogen-free water (e.g., WFI USP), before use.The conjugates provided herein may also be formulated in rectalcompositions such as suppositories or retention enemas, using, e.g.,conventional suppository bases such as cocoa butter or other glycerides.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds may be dissolved or suspended in suitable liquids, suchas fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for the chosen route ofadministration.

Quetiapine was originally launched as an immediate release product(Seroquel®) with the following dosage strengths per tablet: 25 mg, 50mg, 100 mg, 200 mg and 300 mg. Recommended daily doses typically rangefrom 150-800 mg depending on indication and individual patienttitration. In another embodiment, quetiapine is available in an extendedrelease formulation (Seroquel XR®) with dosage strengths of 50 mg, 150mg, 200 mg, 300 mg and 400 mg per tablet. Typical daily doses range from300-800 mg.

In one embodiment, the compositions provided herein are formulated fortransdermal delivery, such as a patch in one embodiment. In anotherembodiment, the term “transdermal delivery” refers to the transport ofthe composition comprising the conjugate of quetiapine or an activemetabolite and/or derivative thereof and a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid, a cross-linked fatty acid or acombination thereof across the epidermis, where the compound is absorbedin the blood capillaries. In another aspect, transdermal delivery refersto the administration of the conjugate of quetiapine or an activemetabolite and/or derivative thereof and a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid, a cross-linked fatty acid or acombination thereof in a transdermal therapeutic system, comprising adrug reservoir matrix comprised essentially of a) a gelling agent thatis selected from the group consisting of carbomer, carboxyethylene,polyacrylic acid, cellulose derivatives, ethylcellulose, hydroxypropylmethyl cellulose, ethyl hydrooxyethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, naturalgums, arabic, xanthan, guar gums, alginates, polyvinylpyrrolidonederivatives, polyoxyethylene polyoxypropylene copolymers, chitosan,polyvinyl alcohol, pectin, or veegum; and b) quetiapine, an activemetabolite or derivative thereof and therapeutically acceptable saltsthereof, and mixtures thereof; conjugated to at least one of apermeation enhancer.

In one aspect, a transdermal patch is a skin patch which includes theconjugate of quetiapine, its active metabolite and/or active derivative,their pharmaceutically acceptable salt and/or their combination andwhich may be applied to the skin of the subject. Many types of materialsand designs for the transdermal drug delivery have been extensivelydescribed, see e.g., D. Hsien, “Multiple Lamination for TransdermalPatches,” Controlled Released Systems Fabrication Technology, v. 1, pp.167-188 (1988), incorporated herein by reference in its entirety.

In one embodiment, the compositions comprising the conjugates ofquetiapine or an active metabolite and/or derivative thereof and asaturated fatty acid, a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid, across-linked fatty acid or a combination thereof described herein aretransferred by diffusion, in the presence of permeation enhancers inanother embodiment. In other aspects, the conjugate of quetiapine or anactive metabolite and/or derivative thereof and a saturated fatty acid,a monounsaturated fatty acid, a polyunsaturated fatty acid, anacetylenic fatty acid, a substituted fatty acid, a heteroatom containingfatty acid, a ring containing fatty acid, a cross-linked fatty acid or acombination thereof described herein may be transferred from thetransdermal patch by iontophoresis or electroosmosis in other discreteaspects of the transfer mode encompassed by the systems describedherein. Iontophoresis is based on the transport of charged ions bycoulombic attraction/repulsion in an electric field. In one embodiment,iontophoresis induces an increased migration of ions or chargedmolecules such as salts of the conjugates described herein in anelectrolyte medium in the presence of the flow of electric current. Manytransdermal patches which utilize iontophoresis for transport of drugshave been described such as, for example, U.S. Pat. No. 5,527,797,incorporated herein by reference in its entirety.

To effectively permeate the skin in a transdermal delivery system, thedrug sought to be delivered should pass through the stratum corneum(SC), a protective layer of skin that is significantly resistant topermeation of hydrophilic material. In one embodiment, passive drugdiffusion is enhanced through modification of the nature of the drugmolecule to facilitate permeation, such as the conjugation of the API toat least one fatty acid. In another aspect, the fatty acid conjugated toquetiapine and/or its active metabolite and/or its active derivative(s)used in the transdermal delivery systems described herein is ashort-chain fatty acid such as valproic acid in one embodiment, amedium-chain fatty acid such as lauric acid in another embodiment, along-chain fatty acid such as stearic acid in another embodiment, or acombination thereof in yet another embodiment. In another embodiment,the fatty acid conjugated to quetiapine and/or its active metaboliteand/or its active derivative(s) used in the transdermal delivery systemsdescribed herein is a saturated fatty acid, a monounsaturated fattyacid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, or a ringcontaining fatty acid, or a combination thereof.

The term “stratum corneum” is used herein in its broadest sense to referto the outer layer of the skin, which is comprised of (approximately of15) layers of terminally differentiated keratinocytes made primarily ofthe proteinaceous material keratin arranged in a ‘brick and mortar’fashion with the mortar being comprised of a lipid matrix made primarilyfrom cholesterol, ceramides and long chain fatty acids. The stratumcorneum creates the rate-limiting barrier for diffusion of the APIacross the skin.

Accordingly and in one embodiment, provided herein is a quetiapinetransdermal therapeutic system, comprising a drug reservoir comprisedessentially of a) a gelling agent that is selected from the groupconsisting of carbomer in one embodiment, or carboxyethylene,polyacrylic acid, cellulose derivatives, ethyl cellulose, hydroxypropylmethyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, natural gums, arabic,xanthan, guar gums, alginates, polyvinylpyrrolidone derivatives,polyoxyethylene polyoxypropylene copolymers, chitosan, polyvinylalcohol, pectin, or veegum, or their combination in other discreteembodiments; and b) quetiapine, an active metabolite or derivativethereof and therapeutically acceptable salts thereof, and mixturesthereof; conjugated to at least one of a permeation enhancer.

In one embodiment, the term “drug reservoir” refers to a compositionmade to retain and release a conjugate of quetiapine for transdermaldelivery, which composition is produced by combining the conjugate ofquetiapine and a matrix material. The drug reservoir can be a solidreservoir layer, a solid reservoir adhesive layer, or a liquid reservoirlayer containing quetiapine conjugate. In some embodiments, theconjugate of quetiapine reservoir can be a solid reservoir layer of theconjugate of quetiapine in a multilaminate transdermal delivery medicaldevice. When combined with an adhesive, the conjugate of quetiapinereservoir can also be a solid reservoir adhesive layer, which can beused, for example, in a monolith transdermal quetiapine conjugatedelivery medical device. The conjugate of quetiapine reservoir can alsocomprise permeation enhancers, plasticizers, and any other suitableadditive, unless otherwise noted.

In certain discrete embodiments, the matrix compositions of thetransdermal conjugated quetiapine delivery system can, optionally, alsocontain agents known to accelerate the delivery of the conjugate ofquetiapine through the skin. These agents are referred to as skinpenetration enhancers, accelerants, adjuvants, and sorption promoters,and are collectively referred herein as “permeation enhancers.” Thisclass of agents includes, but is not limited to those with diversemechanisms of action including those which have the function ofimproving the solubility and diffusivity of the conjugate of quetiapinewithin the multiple polymer and those which improve percutaneousabsorption, for example, by changing the ability of the stratum corneumto retain moisture, softening the skin, improving the skin'spermeability, acting as penetration assistants or hair follicle openersor changing the state of the skin including the boundary layer. Some ofthese agents have more than one mechanism of action, but in essence theyserve to enhance the delivery of the conjugate of quetiapine, its activemetabolites and/or active derivatives.

In another embodiment, the term “permeation enhancer” refers to an agentor a mixture of agents that increases the permeability of the skin tothe conjugate of quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination. In yet another aspect, the term “permeation enhancer”refers to the increase in the permeability of skin to the conjugate ofquetiapine, its active metabolite and/or active derivative, theirpharmaceutically acceptable salt and/or their combination in thepresence of a permeation enhancer as compared to permeability of skin tothe conjugate quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination in the absence of a permeation enhancer.

In one embodiment, the permeation enhancer conjugated to quetiapine, itsactive metabolite and/or active derivative, their pharmaceuticallyacceptable salt and/or their combination is at least one of across-linked fatty acid. In another embodiment, the permeation enhancerconjugated to quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination is a short-chain fatty acid such as acetic acid in oneembodiment, a medium-chain fatty acid such as capric acid in anotherembodiment, a long-chain fatty acid such as linoleic acid in anotherembodiment, or a saturated fatty acid, a monounsaturated fatty acid, apolyunsaturated fatty acid, an acetylenic fatty acid, a substitutedfatty acid, a heteroatom containing fatty acid, or a ring containingfatty acid in other discrete embodiments of the permeation enhancerconjugated to quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination used in the systems and methods described herein. In anotherembodiment, the term “Fatty acid permeation enhancers” refer to fattyacids of C₄-C₃₀ in one embodiment, or C₁₀-C₂₄ in another embodiment thatare effective to increase aggregate transdermal delivery of therespective conjugate of quetiapine, its active metabolite and/or activederivative, their pharmaceutically acceptable salt and/or theircombination.

In one aspect, the configuration of the transdermal conjugate ofquetiapine delivery systems described herein can be in any shape or sizeas is necessary or desirable. Patch sizes are: from 5 to 60 cm². Inorder to deliver quetiapine at the required rate for the desiredduration, the loading of quetiapine in the patch should be sufficient tomaintain saturation of the drug.

In one embodiment a single dosage unit has a surface area in the rangeof 3.5 cm² to deliver between about 25 and about 60 mg of the quetiapineconjugate per day. In order to maintain saturation for seven days, thepatch contains between about 175 and about 420 mg of the quetiapineconjugate (7 days×25-60 mg/day) in excess of the quantity needed tosaturate the patch with the conjugate of quetiapine. As provided herein,in one embodiment, quetiapine, its active metabolite and/or its activederivative is conjugated to a saturated fatty acid, a monounsaturatedfatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, or a ringcontaining fatty acid, or in another aspect to a functionalized fattyacid, wherein the functionalized fatty acid is cross-linked, forming agel matrix, such as a polyunsaturated fatty acid in one embodiment or amixture of hydroxy fatty acids and dicarboxylic fatty acids in anotherembodiment. Assuming an acceptable weight for the matrix/quetiapine is25-40 mg/cm² it would require a patch of between about 7-11 cm², orbetween about 1 and about 2.6 in² to maintain the desired weekly releaserate, since the reservoir matrix, is structurally saturated with theconjugate of quetiapine.

In one embodiment, the conjugate of quetiapine or an active metaboliteand/or an active derivative thereof and at least one of a saturatedfatty acid, a monounsaturated fatty acid, a polyunsaturated fatty acid,an acetylenic fatty acid, a substituted fatty acid, a heteroatomcontaining fatty acid, a ring containing fatty acid, a cross-linkedfatty acid, a salt thereof, a derivative thereof or their combination ispresent in an amount that produces plasma concentrations of quetiapineor its active metabolite and/or active derivative thereof between about89% and about 115% of the plasma concentrations achieved after oraladministration of an amount of between about 1 mg and about 2000 mg perunit dose.

In another aspect, the fatty acid conjugated to quetiapine and/or itsactive metabolite and/or its active derivative(s) used in thetransdermal delivery systems described herein; is at least one of asaturated fatty acid, a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing fatty acid, or across-linked fatty acid. In another aspect, the fatty acid conjugated toquetiapine and/or its active metabolite and/or its active derivative(s)used in the transdermal delivery systems described herein; is at leastone of an alkyl-substituted, hydroxy-substituted, carboxy-substituted,sulfate-substituted, methoxy-substituted, acetoxy-substituted,aldehyde-substituted, halogenated, nitro-substituted, keto-substitutedfatty acid, or a fatty acid containing at least one three-membered ring,a fatty acid containing at least one five-membered ring, a fatty acidcontaining at least one six-membered ring, a fatty acid containingladderanes, a fatty acid containing at least one furan ring or acombination thereof in other discrete embodiments of the fatty acidconjugated to quetiapine and/or its active metabolite and/or its activederivative(s) used in the transdermal delivery systems described herein.

In one embodiment, the term “cross-linked fatty acid” refers to theinsertion of a functional moiety capable of imparting on the underlyingfatty acid properties that were not present in the non-functional fattyacid. These functions include in one embodiment, but by no means arelimited to; polymerization, cross-linking, ligand attachment site andthe like. In another embodiment, the cross-linked fatty acid is selectedfrom the group consisting of any one of the functionalizable fatty acidcompounds set forth in Tables II-VII.

In one embodiment, the conjugate of quetiapine transdermal therapeuticsystem, comprising a drug reservoir comprised essentially of a) agelling agent; and b) quetiapine, an active metabolite or derivativethereof and therapeutically acceptable salt thereof, and mixturesthereof; conjugated to at least one of a permeation enhancer such as amedium chain fatty acid; further comprise a non-permeable backing and apermeable membrane located between the release matrix and a site ofinterest on the skin of a subject. In another embodiment backingmaterials comprise plastic films of polyethylene, vinyl acetate resins,ethylene vinyl acetate (EVA) copolymers, polyvinyl chloride,polyurethane, and the like, metal foils, non-woven fabric, cloth andcommercially available laminates. In another aspect, the backingmaterial has a thickness in the range of 2, to 3000 micrometers. Incertain embodiments, the backing material is substantially impermeableto the conjugate of quetiapine contained in the reservoir layer. Inanother embodiment, the backing is a multi-layer polymer film containinga layer of aluminum. In one aspect, the backing material comprises amultilaminate of polyethylene terephthalate (PET) and polyethylene vinylacetate (PEVA) copolymer. Numerous examples of appropriate backingmaterials are recognized in the art. In some embodiments, the backing isopaque. Some non-limiting, specific examples of backing materialsinclude: (1) a PET backing material with a sealable layer of EVA (e.g.,12% vinyl acetate, VA) coated on one side of the PET backing material;(2) a film comprising layers of low density PET, nylon, EVA, andethylene vinyl alcohol; (3) a film comprising layers of low densitypolyethylene, nylon and EVA; (4) a bilayer film comprising low densitypolythethylene and nylon; (5) a monolayer of polyethylene; or (6) amonolayer of PET.

In another embodiment, patches provided herein include an outer layer(or “backing layer”) that is distal to the skin. A reservoir patchincludes in one embodiment a reservoir of the conjugate of quetiapinewhere the reservoir is defined by the backing layer and a permeablelayer of material that contacts the skin and allows the prodrug to passthere through.

In one embodiment, the compositions described herein are used in thetransdermal quetiapine conjugate delivery system described herein andare used in the methods provided herein. Accordingly and in anotherembodiment, provided herein is use of a conjugate of quetiapinetransdermal therapeutic system, comprising a drug reservoir comprisedessentially of a) a gelling agent that is quetiapine, its activemetabolite and/or its active derivative conjugated to a cross-linkedfunctionalized fatty acid capable of forming a gel matrix; and b)quetiapine, an active metabolite or derivative thereof andtherapeutically acceptable salt thereof, and mixtures thereof;conjugated to at least one of a permeation enhancer, for the treatmentof a neuropsychiatric disorder, such as schizophrenia. In anotheraspect, the neuropsychiatric disorder is bipolar disorder,obsessive-compulsive disorder, post-traumatic stress disorder, restlesslegs syndrome, autism, alcoholism, depression, insomnia or Tourettesyndrome in other embodiments of the neuropsychiatric disorders usingthe quetiapine transdermal therapeutic system described herein.

In one embodiment, the conjugate of quetiapine, its antipsychotic-activemetabolite and a saturated fatty acid, a monounsaturated fatty acid, apolyunsaturated fatty acid, an acetylenic fatty acid, a substitutedfatty acid, a heteroatom containing fatty acid, a ring containing fattyacid, a cross-linked fatty acid or a combination thereof used in thecompositions provided herein, a salt thereof, a derivative thereof ortheir combination is present in an amount of between about 1 mg and 3000mg per dose form such as for oral, transdermal, rectal, intrathecal orparenteral administration. In another embodiment, quetiapine or itsantipsychotic-active metabolite conjugates, their salts orpharmaceutically acceptable salts are present in the compositionsprovided herein in an amount that is therapeutically effective. In oneembodiment, quetiapine or its antipsychotic-active metaboliteconjugates, their salts or pharmaceutically acceptable salts are presentin the compositions provided herein in an amount of between about 150and 800 mg per dose form. In one embodiment, quetiapine or itsantipsychotic-active metabolite conjugates, their salts orpharmaceutically acceptable salts are present in the compositionsprovided herein in an amount of between about 1 and 100 mg per doseform, or between about 100 and 200 mg/dose, or between about 200 and 300mg/dose, or between about 300 and 400 mg/dose, or between about 400 and500 mg/dose, or between about 500 and 600 mg/dose, or between about 600and 700 mg/dose, or between about 700 and 800 mg/dose, or between about800 and 900 mg/dose, or between about 900 and 1000 mg/dose, or betweenabout 350 and 400 mg/dose, or between about 20 and 30 mg/dose, orbetween about 50 and 150 mg/dose, or between about 1 and 375 mg/dose,each a discrete embodiment of the amount quetiapine or itsantipsychotic-active metabolite conjugates, their salt orpharmaceutically acceptable salt are present in the compositionsprovided herein. In one embodiment, quetiapine or itsantipsychotic-active metabolite conjugates, their salts orpharmaceutically acceptable salts are present in the compositionsprovided herein in an amount of between about 1000 and 2000 mg per doseform. In another embodiment, quetiapine or its antipsychotic-activemetabolite conjugates, their salts or pharmaceutically acceptable saltsare present in the compositions provided herein in an amount of betweenabout 1000 and 1250 mg per dose form, or between about 1250 and 1500 mgper dose form, or between about 1500 and 1750 mg per dose form, orbetween about 1750 and 2000 mg per dose form, or between about 1000 and1500 mg per dose form, or between about 1500 and 2500 mg per dose form,or between about 1000 and 3000 mg per dose form, or between about 2000and 3000 mg per dose form, or between about 2500 and 3000 mg per doseform in other discrete embodiments.

Doses of the fatty acid-quetiapine conjugate prodrugs described hereincan be higher or lower than doses of unconjugated quetiapine dependingon their molecular weight, the respective weight-percentage ofquetiapine as part of the whole conjugate or conjugate salt and theirbioavailability (with respect to released quetiapine). Dose conversionfrom quetiapine fumarate to quetiapine prodrug are performed in oneembodiment, using the following formula:

Dose(QTP prodrug)=f _(BA)×[dose(QTP hemifumarate)×(molecular weight(QTPprodrug)/441.95 g/mol]

Wherein:

QTP=quetiapinef_(BA)=correction factor accounting for differences in bioavailabilitybetween unmodified quetiapine and the compositions comprising theprodrugs described herein. This correction factor is specific for eachprodrug with f_(BA)1 in certain embodiments. In one embodiment, theconjugate of quetiapine, an active metabolite or derivative thereof anda saturated fatty acid, a monounsaturated fatty acid, a polyunsaturatedfatty acid, an acetylenic fatty acid, a substituted fatty acid, aheteroatom containing fatty acid, a ring containing, a cross-linkedfatty acid or a combination thereof is present in an amount calculatedaccording to the formula provided herein, referred to as “equivalentdose” to certain unconjugated quetiapine doses.

In another aspect, the amount per unit dose is based on the content ofquetiapine or active metabolite thereof in the conjugate of quetiapineor an active metabolite and/or an active derivative thereof and at leastone fatty acid, a salt thereof, a derivative thereof or theircombination.

Quetiapine is a dibenzothiazepine derivative. In pharmacokinetic studiesquetiapine is rapidly absorbed after oral administration, with mediantime to reach maximum observed plasma concentration ranging from 1 to 2hours. Absolute bioavailability is estimated at 9%, with a relativebioavailability from orally administered tablets compared with asolution of almost 100%. Administration with food other than high-fatfoods, has minimal effects on the absorption of the API. The drug isapproximately 83% bound to serum proteins. Linear pharmacokinetics isobserved in the clinical dose range (up to 375 mg twice daily). Theterminal half-life time for the drug's elimination is about 7 hours,with the primary route of elimination being through hepatic metabolism.

In one embodiment, the term “relative bioavailability” refers toAUC_((0-∞)) for a specific orally administered composition expressed asa percentage of AUC_((0-∞)) for an orally administered solution of theactive ingredient at the same dosage rate. The term “C_(max)” refers tothe maximum observed blood plasma concentration or the maximum bloodplasma concentration calculated or estimated from a concentration/timecurve, and in one aspect, is expressed in units of ng/ml. The term“T_(max)” refers to the time after administration at which C_(max)occurs, and is expressed in units of hours (h).

In one embodiment, relative bioavailability of the compositionsdescribed herein is increased by between about 9 and 100% whenadministered orally compared with oral administration of unconjugatedquetiapine, an active metabolite and/or an active derivative thereof. Inanother embodiment, the relative bioavailability is increased by betweenabout 25 and 100%, or between about 50 and 100%, or between about 75 and100%, or between about 100 and 125%, or between about 125 and 150%, orbetween about 150 and 175%, or between about 175 and 200%, or betweenabout 9 and 25%, when administered orally compared with oraladministration of unconjugated quetiapine, an active metabolite and/oran active derivative thereof in other discrete embodiments.

Quetiapine is metabolized in one embodiment by cytochrome P450 (CYP) 3A4and/or 2D6 in certain other embodiments. Eleven metabolites wereidentified as formed through hepatic conversion, with three of thosefound to be pharmacologically active. In one embodiment, the metabolitesare conjugated to the fatty acids described herein and are administeredeither alone or in combination with other quetiapine conjugatecompositions described herein and used in the methods and systemsdescribed. Accordingly, in one embodiment, provided herein is acomposition for treating a psychiatric disorder in a subject, comprisinga conjugate of 7-hydroxy-quetiapine (7-OH-QTP) represented by thestructure of Formula II:

and a fatty acid, a salt thereof, a derivative thereof or theircombination. In another embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate ofN-desalkyl-quetiapine (nor QTP) represented by the structure of FormulaIII:

and a fatty acid, a salt thereof, a derivative thereof or theircombination. In another embodiment, provided herein is a composition fortreating a psychiatric disorder in a subject, comprising a conjugate of7-hydroxy-N-desalkyl-quetiapine (7-OH-nor QTP) represented by thestructure of Formula IV:

and an fatty acid, a salt thereof, a derivative thereof or theircombination.

In one embodiment, oral clearance of unconjugated quetiapine declineswith age. In another embodiment, relative bioavailability of fattyacid-quetiapine conjugates is higher at every age, thereby leading toreduced dosage requirements for every indication and minimizingside-effects. Since quetiapine is primarily metabolized by CYP3A4 and/orCYP2D6, dosage adjustment may be necessary in another embodiment whencoadministered with phenyloin, thioridazine, retinoic acid, rifampicin,ketoconazole, carbamazepine or other potent CYP3A4 agonists, antagonistsor modulators. Similarly, dosage adjustment may be necessary in anotherembodiment when coadministered with dextromethorphan, aripiprazole,donepezil, paroxetine, lasofoxifene, risperidone or other potent CYP2D6agonists, antagonists or modulators. In one embodiment, the choice offatty-acid conjugated to quetiapine will affect the dosage adjustmentnecessary.

Advantages

Conjugation of quetiapine or an active metabolite thereof to fatty acidsas described herein, has a number of advantages that may include:

-   -   1. Reduced interindividual variability in plasma concentrations        vs. free quetiapine    -   2. Increased bioavailability    -   3. Improved side-effect profile    -   4. Less potentially toxic metabolites    -   5. Less inactive metabolites    -   6. Improved solubility in organic solvents    -   7. Reduced potential for drug abuse

In one embodiment, the compositions comprising quetiapine conjugated toa fatty acid, further comprise a carrier, excipient, lubricant, flowaid, processing aid or diluent, wherein said carrier, excipient,lubricant, flow aid, processing aid or diluent is a gum, starch, asugar, a cellulosic material, an acrylate, calcium carbonate, magnesiumoxide, talc, lactose monohydrate, magnesium stearate, colloidal siliconedioxide or mixtures thereof.

In another embodiment, the composition further comprises a binder, adisintegrant, a buffer, a protease inhibitor, a surfactant, asolubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, aviscosity increasing agent, a sweetener, a film forming agent, or anycombination thereof.

In one embodiment, the composition is a controlled release composition.In another embodiment, the composition is an immediate releasecomposition. In one embodiment, the composition is a liquid dosage form.In another embodiment, the composition is a solid dosage form.

In one embodiment, the term “pharmaceutically-acceptable salts” embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts of compounds of thefatty acid-quetiapine conjugates described herein, are prepared inanother embodiment, from an inorganic acid or from an organic acid.Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically acceptablebase addition salts include metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc or organic salts madefrom N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. All of these salts may be prepared by conventional means fromthe corresponding compound by reacting, in another embodiment, theappropriate acid or base with the compound.

In one embodiment, the term “pharmaceutically acceptable carriers”includes, but is not limited to, 0.01-0.1M and preferably 0.05Mphosphate buffer, or in another embodiment 0.8% saline. Additionally,such pharmaceutically acceptable carriers may be in another embodimentaqueous or non-aqueous solutions, suspensions, and emulsions. Examplesof non-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. In one embodiment the concentration of phosphate buffer used as apharmaceutically acceptable carrier is between about 0.01 to about 0.1M,or between about 0.01 to about 0.09M in another embodiment, or betweenabout 0.01 to about 0.08M in another embodiment, or between about 0.01to about 0.07M in another embodiment, or between about 0.01 to about0.06M in another embodiment, or between about 0.01 to about 0.05M inanother embodiment, or between about 0.01 to about 0.04M in anotherembodiment, or between about 0.01 to about 0.03M in another embodiment,or between about 0.01 to about 0.02M in another embodiment, or betweenabout 0.01 to about 0.015 in another embodiment.

The pharmaceutical preparations comprising the compositions used in oneembodiment in the methods provided herein can be prepared by dissolving,mixing, granulating, or tablet-forming processes. For oraladministration, the active ingredients, or their physiologicallytolerated derivatives in another embodiment, such as salts, esters,N-oxides, and the like are mixed with additives customary for thispurpose, such as vehicles, stabilizers, or inert diluents, and convertedinto suitable forms for administration, such as tablets, coated tablets,hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.Examples of suitable inert vehicles are conventional tablet bases suchas lactose, sucrose, or cornstarch in combination with binders such asacacia, cornstarch, gelatin, with disintegrating agents such ascornstarch, potato starch, alginic acid, or with a lubricant such asstearic acid or magnesium stearate.

Examples of suitable oily vehicles or solvents are vegetable or animaloils such as sunflower oil or fish-liver oil. Preparations can beeffected both as dry and as wet granules. For parenteral administration(subcutaneous, intravenous, intraarterial, or intramuscular injection),the active ingredients or their physiologically tolerated derivativessuch as salts, esters, N-oxides, and the like are converted into asolution, suspension, or emulsion, if desired with the substancescustomary and suitable for this purpose, for example, solubilizers orother auxiliaries. Examples are sterile liquids such as water forinjection and oils, with or without the addition of a surfactant andother pharmaceutically acceptable adjuvants. Illustrative oils are thoseof petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, or mineral oil. In general, water, saline,aqueous dextrose and related sugar solutions, and glycols such aspropylene glycols or polyethylene glycol are preferred liquid carriers,particularly for injectable solutions. In one embodiment, using fattyacid conjugates, increases solubility or dispersibility of quetiapine,its active metabolite and/or derivative in the oily vehicles describedherein.

In addition, the compositions described in the embodiments providedherein, can contain minor amounts of auxiliary substances such aswetting or emulsifying agents, pH buffering agents which enhance theeffectiveness of the active ingredient.

The fatty acid-quetiapine conjugate described herein is administered inanother embodiment, in a therapeutically effective amount. The actualamount administered, and the rate and time course of administration,will depend in one embodiment, on the nature and severity of thecondition being treated. Prescription of treatment, e.g., decisions ondosage, timing, etc., is within the responsibility of generalpractitioners or specialists, and typically takes account of thedisorder to be treated, the condition of the individual patient, thesite of delivery, the method of administration and other factors knownto practitioners. Examples of techniques and protocols can be found inRemington's Pharmaceutical Sciences.

The compositions of the present invention are formulated in oneembodiment for oral delivery, wherein the active compounds may beincorporated with excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The tablets, troches, pills, capsules and the like mayalso contain the following: a sweetening agent, such as sucrose, lactoseor saccharin that may be added or a flavoring agent, such as peppermint,oil of wintergreen, or cherry flavoring. When the dosage unit form is acapsule, it may contain, in addition to materials of the types describedhereinabove, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar, or both. Syrup or elixir may contain sucrose as the activesweetening agent, methyl and propylparabens as preservatives, a dye andflavoring, such as cherry or orange flavor. In addition, the API may beincorporated into sustained-release, pulsed release, controlled releaseor postponed release preparations and formulations.

In another embodiment, the term “dosage unit” refers to the portion of apharmaceutical composition that contains a single unit dose of theactive ingredient. For purposes of the disclosure presented herein, adose unit can be in the form of a discrete article such as a tablet orcapsule, or can be a measurable volume of a solution, suspension or thelike containing a unit dose of the active ingredient. The term “unitdose” refers in one embodiment to an amount of active ingredientintended for a single oral administration to a subject for treatment ofa psychiatric condition or disorder. Treatment of a psychiatriccondition or disorder, comprising mediating or binding of a dopamineand/or serotonin and/or histamine receptor, may require periodicadministration of unit doses of the compositions described herein, forexample one unit dose two or more times a day, one unit dose with eachmeal, one unit dose every four hours or other interval, or only one unitdose per day.

Controlled or sustained release compositions include formulations inlipophilic depots (e.g., fatty acids, waxes, oils). Also comprehended bythe invention are particulate compositions coated with polymers (e.g.,poloxamers or poloxamines). In another embodiment, a controlled releasesystem can be placed in proximity to the therapeutic target, i.e., thebrain, thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 [1984]). Other controlled release systems are discussed inthe review by Langer (Science 249:1527-1533 [1990]).

In one embodiment, the carriers for use within such compositions arebiocompatible, and/or biodegradable. In other embodiments, theformulation may provide a relatively constant level of release of oneactive component. In other embodiments, however, a more rapid rate ofrelease immediately upon administration may be desired. In otherembodiments, release of active compounds may be event-triggered. Theevents triggering the release of the active compounds may be the same inone embodiment, or different in another embodiment. Events triggeringthe release of the active components may be exposure to moisture, lowerpH or temperature threshold in other discrete embodiments. Theformulation of such compositions is well within the level of ordinaryskill in the art using known techniques. Illustrative carriers useful inthis regard include microparticles of poly(lactide-co-glycolide),polyacrylate, latex, starch, cellulose, dextran and the like. Otherillustrative postponed-release carriers include supramolecularbiovectors, which comprise a non-liquid hydrophilic core (e.g., across-linked polysaccharide or oligosaccharide) and, optionally, anexternal layer comprising an amphiphilic compound, such asphospholipids. The amount of active compound contained in oneembodiment, within a sustained release formulation depends upon the siteof administration, the rate and expected duration of release and thenature of the condition to be treated, suppressed or inhibited.

In one embodiment, the term “administering” refers to bringing a subjectin contact with the compositions provided herein. For example, in oneembodiment, the compositions provided herein are suitable for oraladministration, whereby bringing the subject in contact with thecomposition comprises ingesting the compositions. A person skilled inthe art would readily recognize that the methods of bringing the subjectin contact with the compositions provided herein, will depend on manyvariables such as, without any intention to limit the modes ofadministration; age, pre-existing conditions, other agents administeredto the subject, the severity of symptoms, subject weight or propensityto gain weight, refraction to other medication and the like. In oneembodiment, provided herein are embodiments of methods for administeringthe compounds of the present invention to a subject, through anyappropriate route, as will be appreciated by one skilled in the art.

Methods of Synthesis

A general synthetic scheme for the synthesis of a prodrug of thisinvention typically consists of the following steps:

-   -   1. Protection of substituents on the fatty acid, if applicable.    -   2. Activation of the carboxylic group, if not already in        activated form.    -   3. Addition of activated fatty acid to quetiapine or vice versa        in the presence of base    -   4. Removal of any protecting groups, if applicable.

Accordingly and in one embodiment, provided herein is a method ofconjugating quetiapine or an active metabolite and/or an activederivative thereof and at least one fatty acid, comprising the steps of:in the presence of a base, attaching a carboxyl activated fatty acid toquetiapine or its active metabolite and/or derivative; followed bydeprotecting the optionally protected fatty acid moiety, therebyconjugating quetiapine or an active metabolite and/or an activederivative thereof and at least one fatty acid

The carboxylic acid group of the fatty acid is activated in oneembodiment in order to react with quetiapine to produce appreciableamounts of conjugate. The fatty acids can be activated in anotherembodiment, by synthesizing esters of N-hydroxy succinimide (NHS). Otheractivating agents include but are not limited to the following:N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI),N,N′-diisopropyl-carbodiimide (DIC), 1,1′-carbonyldiimidazole (CDI) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other aminium-based reagents.

It may be necessary to attach one or more protecting groups to anyadditional reactive functional groups that may interfere with thecoupling to quetiapine. Any suitable protecting group may be useddepending on the type of functional group and reaction conditions. Inone embodiment a protective group is for a thiol, hydroxy, amino orcarboxyl group used in common preparations of the conjugated prodrugsdescribed herein. Suitable protecting group examples include but are notlimited to: acetyl (Ac), tert-butyoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), p-methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl(Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), 3,4 dimethoxybenzyl (DMPM),p-methozyphenyl (PMP), tosyl (Ts), or amides (like acetamides,pthalamides, etc). In another embodiment, the fatty acid residueprotecting group is acetyl, propionyl, butyryl, phenylacetyl, benzoyl,toluoyl, phenoxyacetyl (POA), methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloro-ethoxycarbonyl, 2-iodoethoxycarbonyl,4-methoxybenzyloxycarbonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl(Mtr), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) or2,2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc).

A base may be required at any step of the synthesis of fatty acidconjugates of quetiapine. Suitable bases include but are not limited to4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithiumdiisopropylamide (LDA), any alkali metal tert-butoxide (e.g., potassiumtert-butoxide), any alkali metal hydride (e.g., sodium hydride), anyalkali metal alkoxide (e.g., sodium methoxide), triethylamine or anyother tertiary amine.

An acid may be required to remove certain protecting groups. Suitableacids include but are not limited to hydrochloric acid, hydrobromicacid, hydrofluoric acid, hydriodic acid, sulfuric acid, phosphoric acid,trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid,p-toluenesulfonic acid and nitric acid.

Appropriate solvents that can be used for any reaction in the syntheticscheme of any fatty acid conjugate of quetiapine include but are notlimited to: acetone, acetonitrile, butanol, chloroform, dichloromethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol,ethyl acetate, diethyl ether, heptane, hexane, methanol, methyltert-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropylether, tetrahydrofuran, toluene, xylene or water.

In one embodiment, the compounds conjugated using the methods providedherein, are used in the compositions, transdermal delivery systems andmethods described herein. Accordingly, and in another embodiment,provided herein is a quetiapine, its active metabolite and/orderivative; conjugated to a saturated fatty acid, a monounsaturatedfatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, a ringcontaining fatty acid, a cross-linked fatty acid, or a combinationthereof synthesized by attaching a fatty acid in the presence of a baseto quetiapine or its active metabolite and/or derivative; followed byoptionally deprotecting any functional moiety on the fatty acid moiety,thereby conjugating quetiapine, an active metabolite and/or an activederivative thereof and a fatty acid.

In one embodiment, the compositions described herein are used to carryout the methods provided herein.

In one embodiment, the psychiatric disorder sought to be treated usingthe compositions provided herein is bipolar disorder (BPD) and theinpatient receives conjugated valproate-quetiapine at an equimolar dosein the amount of 375 mg daily of unconjugated quetiapine, correspondingto a dose of over 375 mg daily due to the higher bioavailability of theconjugated quetiapine as described herein, leading to a largerdifference and shorter duration in depressive symptoms on admission andat discharge using the Beck-Rafaelsen Mania Scale (MAS) and/or theMontgomery Asberg depression rating scale (MADRS), respectively.

In another aspect, valproic acid is becoming an increasingly commonagent to be taken in overdose, with a sharp rise in incidence over thelast 5 years (e.g., divalproex). This is likely to be a result of thebroadening clinical uses of valproate, including its use as a moodstabilizer in patients with bipolar and affective disorders. Valproicacid is FDA approved for the treatment of acute manic episodes. Itsresponse rate in acute mania is around 50%, compared to a placebo effectof 20-30%. Patients respond relatively rapidly (within 1-2 weeks andoften a few days). Valproate appears to have a more robust antimaniceffect than lithium in rapid cycling and mixed episodes. Concerningbipolar depression, there is inconsistent data regarding its efficacywith some data suggesting reduced effectiveness compared to mania(response rate close to 30%). Although valproate seems to havesignificant prophylactic antimanic properties, its prophylacticantidepressant ones are low to moderate. In one embodiment, conjugatingvalproic acid to quetiapine as described herein, creates a novel mutualprodrug API that increases the efficacy of valproate AND quetiapine as asingle API mood stabilizer, reduces the risk of overdosing or theircombination. Accordingly and in one embodiment, provided herein is theuse of quetiapine, its active metabolite and/or active derivative,conjugated to valproic acid in a composition for the treatment ofdisorders including, but not limited to, absence seizures, tonic-clonicseizures (grand mal), complex partial seizures, juvenile myoclonicepilepsy; seizures associated with Lennox-Gastaut syndrome, myoclonus,rapid cycling bipolar disorder, bipolar disorder associated mania,bipolar disorder associated depression or their combination.

The term “mutual prodrug” in one embodiment is interchangeable with theterm “codrug” referring in one embodiment to a chemically modifiedtherapeutic agent, which consists of two drugs covalently linkedtogether in order to modulate the drug delivery, metabolism, stabilityor a combination thereof of one or both drugs. In another embodiment,the codrug consists of two pharmacologically active drugs that arecoupled together in a single molecule, so that each drug acts as apromoiety for the other. In one embodiment, the advantage of using thetransdermal valproate-quetiapine codrug; which can undergo bioconversionto the active parent drugs, is that the skin irritation and allergenicpotential of the codrug should only mirror the profile of the activeparent drugs, without the added toxicities of additional penetrationenhancers or active transport devices. Because the skin and plasma havean abundance of esterase enzymes, codrugs with esterase-susceptiblelinkages such as the valproate-quetiapine conjugate provided herein, canbe cleaved by these enzymes to release the active parent drugs in the CStissue and plasma.

Therapeutically effective serum concentrations of valproic acid rangebetween 50 and 150 mg/mL. Side-effects from administration of valproicacid comprise gastrointestinal symptoms in one embodiment, or sedation,tremor, weight gain, hair loss, ataxia, dysarthria or persistentelevation of hepatic transaminases in other discrete embodiments of theadverse side-effects capable of being eliminated, ameliorated or reducedusing quetiapine, its active metabolite and/or active derivative,conjugated to valproic acid compositions provided herein.

In another embodiment, the psychiatric disorder sought to be treatedusing the compositions provided herein is schizophrenia, and theinpatient receives conjugated quetiapine at an equimolar dose in theamount of 450 mg daily of unconjugated quetiapine, corresponding to adose of over 450 mg daily due to the higher bioavailability of theconjugated quetiapine as described herein, leading to a largerdifference and shorter duration in depressive symptoms on admission andat discharge using Brief Psychiatric Rating Scale (BPRS), ClinicalGlobal Impression (CGI), Positive And Negative Syndrome Scale (PANSS)and the like. Using the compositions described herein, results inanother embodiment in increased intervals between psychotic episodes,decrease in severity of the episodes and a lesser loss in cognitiveabilities following an episode.

In one embodiment, provided herein is a method of treating a psychiatricdisorder involving the binding to dopamine receptor(s), serotoninreceptor(s), norepinephrine receptor(s) or a combination and/orpermutation thereof in a subject, comprising the step of administeringto the subject a composition comprising a therapeutically effectiveamount of quetiapine, an active metabolite and/or an active derivativethereof, conjugated to at least one fatty acid, a pharmaceuticallyacceptable salt or derivative thereof, thereby binding to dopaminereceptor(s), serotonin receptor(s), or norepinephrine receptor(s) or acombination and/or permutation thereof.

In another embodiment, provided herein is a method of treatingschizophrenia or bipolar disorder in a subject in need thereof,comprising the step of administering to the subject a compositioncomprising a therapeutically effective amount of quetiapine, an activemetabolite and/or an active derivative thereof, conjugated to at leastone fatty acid, a pharmaceutically acceptable salt or derivativethereof, thereby binding to dopamine receptor(s), serotonin receptor(s),or both.

In another embodiment, due to the higher relative bioavailability, theunit dose used for treating the disorders described herein will beadjusted downward, leading to a decrease in number and severity ofside-effects.

In one embodiment, the disorder requiring the binding to dopaminereceptor(s), serotonin receptor(s), or both in a subject isobsessive-compulsive disorder (OCD), post-traumatic stress disorder(PTSD), restless legs syndrome, autism, alcoholism, depression,insomnia, hyperprolactinemia or Tourette syndrome.

By way of example, restless leg syndrome (RLS) has been treated withnon-ergot dopamine agonists, with quetiapine showing remarkableefficacy. In one embodiment, provided herein is a method of treating RLSin a subject in need thereof, comprising the step of orallyadministering to the subject a therapeutically effective amount of acomposition comprising quetiapine, an active metabolite and/or activederivative thereof conjugated to a saturated fatty acid, amonounsaturated fatty acid, a polyunsaturated fatty acid, an acetylenicfatty acid, a substituted fatty acid, a heteroatom containing fattyacid, a ring containing fatty acid or a combination thereof, apharmaceutically acceptable salt thereof or their combination.

Likewise and in another embodiment, post-traumatic stress disorder(PTSD) refers in one embodiment to a chronic mental illness, causingoccupational disability, psychiatric and medical morbidity and severepsychosocial distress. The prevalence of PTSD in the general populationin the U.S. was estimated to be 7.8% in 2006. Core symptoms of PTSDinclude recurrent re-experiencing of the trauma in the form of intrusivememories, nightmares and flashbacks; avoidant behaviors; and autonomicarousal. In addition to the core PTSD symptoms, patients with PTSD alsoexhibit irritability, impulsivity, depression and aggression. PTSD isoften difficult to treat, with recent initiatives focusing on the roleof serotonin in the neuroregulation of PTSD. The neurotransmitterserotonin influences mood, aggression, arousal, anxiety, sleep,learning, nociception, fear and appetite. Likewise, dopamineneurotransmission dysfunction has been shown to be responsible forsymptoms such as paranoia, hallucinations, increased startle responseand their combination. Physiologically, the density of plateletserotonin-uptake sites, as determined by paroxetine binding, wassignificantly decreased in patients with PTSD, compared with normalcontrols. Clinical studies showed the benefits of treatment of PTSDsymptoms with a 5-HT_(1A) partial agonist, of which quetiapinemetabolite N-desalkyl-quetiapine is one.

In one embodiment, the term “treating” refers to abrogating,substantially inhibiting, slowing or reversing the progression of adisease, substantially ameliorating clinical symptoms of a disease orsubstantially preventing or delaying the appearance of clinical symptomsof a disease.

In one embodiment, the compositions provided herein, which in anotherembodiment are used in the methods described herein; are administered toa subject in need thereof as part of a combination therapy with othermedication that is specific for the indication sought to be treated. Aperson skilled in the art would readily recognize that combinationtherapy as described in the methods and compositions provided herein,could be administered either simultaneously or consecutively and so longas they are administered for the same indication, would be encompassedby the description provided herein.

Accordingly and in certain embodiments, lithium and/or divalproex areused as adjunct therapies with the compositions provided herein.

Another embodiment provided herein is the use of a therapeuticallyeffective amount of a conjugate of quetiapine, its active metaboliteand/or active derivative; and a saturated fatty acid, a monounsaturatedfatty acid, a polyunsaturated fatty acid, an acetylenic fatty acid, asubstituted fatty acid, a heteroatom containing fatty acid, a ringcontaining fatty acid or a combination thereof in a medicament for thetreatment of a disorder associated with serotonin, dopamine ornorepinephrine dysfunction in a subject in need thereof.

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

In one embodiment, the term “subject” refers to a mammal including ahuman in need of therapy for, or susceptible to, a condition or itssequelae. The subjects may include dogs, cats, pigs, cows, sheep, goats,horses, rats, mice and humans. The term “subject” does not exclude anindividual that is normal in all respects. In one embodiment, thesubject is a human subject.

The term “about” as used herein means in quantitative terms plus orminus 5%, or in another embodiment plus or minus 10%, or in anotherembodiment plus or minus 15%, or in another embodiment plus or minus20%.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way beconstrued, however, as limiting the broad scope of the invention.

EXAMPLES Example 1 Oral Pharmacokinetic Data

Prodrug conjugates described herein were dosed as oral solutions in ratsand compared to an equimolar solution of quetiapine dihydrochloride.Although the commercial form of quetiapine (Seroquel®) is a fumaratesalt, the dihydrochloride salt was used as comparator because thefumarate is not soluble enough to be dosed efficiently via oral gavagein rats.

Generally and as shown in FIGS. 1-4, plasma concentrations of quetiapinereleased from the prodrugs described herein were compared to plasmaconcentrations generated by an equimolar amount of quetiapinehydrochloride salt. Overall, plasma concentrations of releasedquetiapine varied depending on the attached fatty acid. Exposure rangedfrom 34-121%-AUC compared to quetiapine hydrochloride salt.

Example 2 General Synthesis of Fatty Acid-Quetiapine Conjugates

A general synthetic scheme for the synthesis of a prodrug of thisinvention typically consists of the following steps (See FIG. 5):

-   -   1. Protection of a functional moiety on the fatty acid, if        applicable.    -   2. Activation of the carboxylic group, if not already in        activated form.    -   3. Addition of activated fatty acid to quetiapine or vice versa        in the presence of base    -   4. Removal of protecting groups on functional moieties of the        fatty acid, if applicable.

To a solution of quetiapine freebase (1 mmol) in anhydrous THF (20 mL)was added TEA (3 mmol) and DMAP (0.1 mmol). The solution was stirred andthe fatty acid chloride (1.5 mmol) was added drop wise at roomtemperature. After 2-6 hours, depending on the fatty acid derivative,solvents were evaporated to dryness and the residue was dissolved inethyl acetate (400 mL). The organic phase was washed with aqueous NH₄Cl(2×250 mL) and aqueous NaHCO₃ (2×250 mL), dried over anhydrous Na₂SO₄and evaporated to dryness to yield the fatty acid-quetiapine conjugate.

The conjugate was converted to its hydrochloride salt by stirring with 4N HCl in dioxane for 15 min. at room temperature and evaporating thesolvent to dryness. The residue was triturated with IPAc and theprecipitate was filtered and dried to yield the hydrochloride salt ofthe fatty acid-quetiapine conjugate.

Having described certain embodiments of the invention with reference tothe accompanying drawings, it is to be understood that the invention isnot limited to the precise embodiments, and that various changes andmodifications may be effected therein by those skilled in the artwithout departing from the scope or spirit of the invention as definedin the appended claims.

What is claimed is:
 1. A composition for treating a psychiatric disorderin a subject, comprising a prodrug conjugate of2-(2-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol(quetiapine) and a straight chain, saturated fatty acid having thegeneral formula of C_(n)H_(2n+1)—CO₂H, wherein n is 1-7.
 2. Thecomposition of claim 1, wherein the prodrug conjugate has the followingstructure:


3. The composition of claim 1, wherein n is
 1. 4. The composition ofclaim 1, wherein n is
 4. 5. The composition of claim 1, wherein n is 7.6. The composition of claim 1, wherein the straight chain, saturatedfatty acid is acetate or ethanoate.
 7. The composition of claim 6,wherein the prodrug conjugate has the following structure:


8. The composition of claim 1, wherein the straight chain, saturatedfatty acid is valerate or pentanoate.
 9. The composition of claim 8,wherein the prodrug conjugate has the following structure:


10. The composition of claim 1, wherein the straight chain, saturatedfatty acid is caprylate or octanoate.
 11. The composition of claim 10,wherein the prodrug conjugate has the following structure:


12. The composition of claim 1, wherein the composition has a higherrelative bioavailability than non-conjugated quetiapine whenadministered orally.
 13. The composition of claim 1, wherein the prodrugconjugate is in a salt form selected from the group consisting ofacetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate,L-camsylate, citrate, edisylate, formate, fumarate, gluconate,hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate,D,L-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate,succinate, sulfate, bisulfate, D-tartrate, L-tartrate, D,L-tartrate,meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate,isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate,orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate,aminosalicylate, ascorbate, borate, butyrate, camphorate,camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutamate,glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate,hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate,maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate,oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate,salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate,thiosalicylate, tribrophenate, valerate, valproate, adipate,4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate,thiocyanate, undecylenate; and a mixture thereof.
 14. The composition ofclaim 1, wherein the composition is formulated for oral, sublingual,transdermal, suppository, or intrathecal administration.
 15. Thecomposition of claim 14, wherein the composition formulated for oraladministration is a tablet, capsule, caplet, pill, powder, troche,lozenge, slurry, liquid solution, suspension, emulsion, elixir or oralthin film (OTF).
 16. The composition of claim 1, wherein the prodrugconjugate is present in an amount per unit dose of between about 1 mgand about 2000 mg per unit dose of the composition.
 17. The compositionof claim 16, wherein the prodrug conjugate is present in an amount perunit dose of between about 150 mg and about 800 mg per unit dose of thecomposition.
 18. The composition of claim 16, wherein the amount perunit dose is based on the amount of quetiapine present in the prodrugconjugate; or wherein the amount per unit dose is based on the amount ofquetiapine in a salt of the prodrug conjugate.
 19. The composition ofclaim 1, wherein the psychiatric disorder is at least one ofschizophrenia, bipolar disorder, obsessive-compulsive disorder,post-traumatic stress disorder, restless legs syndrome, autism,alcoholism, depression, insomnia, Tourette syndrome or a combinationthereof.
 20. The composition of claim 1, wherein the subject is a humanor a mammal subject.
 21. The composition of claim 1, wherein the subjecthas not been diagnosed with schizophrenia or bipolar disorder.
 22. Thecomposition of claim 1, further comprising one or more of: lithium,divalproex, adjuvants, antiadherents, binders, coatings, disintegrants,fillers, flavors and colors, glidants, lubricants, preservatives,sorbents, sweeteners or a combination thereof.
 23. The composition ofclaim 1 wherein the composition is a combination of the prodrugconjugate and a salt of the prodrug conjugate.